ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
ADCIRCA 20 mg film-coated tablets
2.
Each tablet contains 20 mg tadalafil.
Excipients: Each coated tablet contains 245 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Orange and almond shaped tablets, marked "4467" on one side.
4.
ADCIRCA is indicated in adults for the treatment of pulmonary arterial hypertension (PAH) classified
as WHO functional class II and III, to improve exercise capacity (see section 5.1).
Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.
Method of administration
ADCIRCA is available as 20 mg film-coated tablets for oral use.
Posology
Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.
The recommended dose is 40 mg (2 x 20 mg) taken once daily with or without food.
Use in elderly patients
Dose adjustments are not required in elderly patients.
Use in patients with renal impairment:
In patients with mild to moderate renal impairment a starting dose of 20 mg once per day is
recommended. The dose may be increased to 40 mg once per day, based on individual efficacy and
tolerability. In patients with severe renal impairment the use of ADCIRCA is not recommended. (See
sections 4.4 and 5.2).
Use in patients with hepatic impairment:
Due to limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh
Class A and B), following single doses of 10 mg, a starting dose of 20 mg once per day may be
considered. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken
by the prescribing physician. Patients with severe hepatic cirrhosis (Child-Pugh Class C)
have not
been studied and therefore dosing of tadalafil is not recommended. (See sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of ADCIRCA in individuals below 18 years of age has not yet been
established. No data are available.
2
Hypersensitivity to the active substance or to any of the excipients.
Acute myocardial infarction within the last 90 days.
Severe hypotension (<90/50 mm Hg).
-
In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is
thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP
pathway. Therefore, administration of ADCIRCA to patients who are using any form of organic
nitrate is contraindicated. (See section 4.5).
ADCIRCA is contraindicated in patients who have loss of vision in one eye because of non-arteritic
anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or
not with previous PDE5 inhibitor exposure (see section 4.4).
The following groups of patients with cardiovascular disease were not included in PAH clinical trials:
- Patients with clinically significant aortic and mitral valve disease
- Patients with pericardial constriction
- Patients with restrictive or congestive cardiomyopathy
- Patients with significant left ventricular dysfunction
- Patients with life-threatening arrhythmias
- Patients with symptomatic coronary artery disease
- Patients with uncontrolled hypertension.
Since there are no clinical data on the safety of tadalafil in these patients, the use of tadalafil is not
recommended.
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with
pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of
tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not
recommended. Should signs of pulmonary oedema occur when tadalafil is administered, the possibility
of associated PVOD should be considered.
As with other PDE5 inhibitors, tadalafil has systemic vasodilatory properties that may result in
transient decreases in blood pressure. Physicians should carefully consider whether their patients with
certain underlying conditions, such as severe left ventricular outflow obstruction, fluid depletion,
autonomic hypotension or patients with resting hypotension, could be adversely affected by such
vasodilatory effects.
Visual defects and cases of NAION have been reported in connection with the intake of ADCIRCA
and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, to
consult a physician immediately (see section 4.3). Patients with known hereditary degenerative retinal
disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these
patients is not recommended.
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to
influence clearance by dialysis, ADCIRCA is not recommended in patients with severe renal
impairment.
3
Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing
of ADCIRCA is not recommended.
Priapism has been reported in men treated with PDE5 inhibitors. Patients who experience erections
lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not
treated immediately, penile tissue damage and permanent loss of potency may result.
ADCIRCA should be used with caution in patients with anatomical deformation of the penis (such as
angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may
predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).
In patients who are taking alpha
1
blockers concomitant administration of ADCIRCA may lead to
symptomatic hypotension in some patients (see section 4.5). Therefore, the combination of tadalafil
and doxazosin is not recommended.
For patients chronically taking potent inducers of CYP3A4, such as rifampicin, the use of tadalafil is
not recommended (see section 4.5).
For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the
use of tadalafil is not recommended (see section 4.5).
The safety and efficacy of combinations of ADCIRCA and other PDE5 inhibitors or other treatments
for erectile dysfunction have not been studied. Inform patients not to take ADCIRCA with these
medications.
The efficacy and safety of tadalafil co-administered with prostacyclin or its analogues has not been
studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.
The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively
demonstrated (see sections 4.5 and 5.1).
ADCIRCA contains lactose monohydrate. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Effects of other substances on tadalafil
Cytochrome P450 Inhibitors
Azole Antifungals
(e.g.
ketoconazole)
Ketoconazole (200 mg daily), increased tadalafil (10 mg) single dose exposure (AUC) 2-fold and C
max
by 15%, relative to the AUC and C
max
values for tadalafil alone. Ketoconazole (400 mg daily)
increased tadalafil (20 mg) single dose exposure (AUC) 4-fold and C
max
by 22%.
Protease inhibitors (e.g. ritonavir)
Ritonavir (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6,
increased tadalafil (20 mg) single dose exposure (AUC) 2-fold with no change in C
max
. Ritonavir
(500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32% and
decreased C
max
by 30%.
Cytochrome P450 Inducers
Endothelin-1 receptor antagonists (e.g. bosentan)
Bosentan (125 mg twice daily), a substrate of CYP2C9 and CYP3A4 and a moderate inducer of
CYP3A4, CYP2C9 and possibly CYP2C19, reduced tadalafil (40 mg once per day) systemic exposure
4
by 42% and C
max
by 27% following multiple dose co-administration. The efficacy of tadalafil in
patients already on bosentan therapy has not been conclusively demonstrated (see sections 4.4 and
5.1). Tadalafil did not affect the exposure (AUC and C
max
) of bosentan or its metabolites.
The safety and efficacy of combinations of ADCIRCA and other endothelin-1 receptor antagonists
have not been studied.
Antimicrobial agents (e.g. rifampicin)
A CYP3A4 inducer, rifampicin (600 mg daily), reduced tadalafil AUC by 88 % and C
max
by 46%,
relative to the AUC and C
max
values for tadalafil alone (10 mg).
Effects of tadalafil on other medicinal products
Nitrates
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of
nitrates. This interaction lasted for more than 24 hours and was no longer detectable when 48 hours
had elapsed after the last tadalafil dose. Therefore, administration of ADCIRCA to patients who are
using any form of organic nitrate is contraindicated (see section 4.3).
Anti-hypertensives (including Calcium channel blockers)
The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a
single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner.
This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore this
combination is not recommended (see section 4.4).
In interaction studies performed in a limited number of healthy volunteers, these effects were not
reported with alfuzosin or tamsulosin.
In clinical pharmacology studies, the potential for tadalafil (10 and 20 mg) to augment the hypotensive
effects of antihypertensive agents was examined. Major classes of antihypertensive agents were
studied either as monotherapy or as part of combination therapy. In patients taking multiple
antihypertensive agents whose hypertension was not well controlled, greater reductions in blood
pressure were observed compared to subjects whose blood pressure was well controlled, where the
reduction was minimal and similar to that in healthy subjects. In patients receiving concomitant
antihypertensive medicines, tadalafil 20 mg may induce a blood pressure decrease, which (with the
exception of doxazosin -see above) is, in general, minor and not likely to be clinically relevant.
Alcohol
Alcohol concentrations were not affected by co-administration with tadalafil (10 mg or 20 mg). In
addition, no changes in tadalafil concentrations were seen after co-administration with alcohol.
Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7 g/kg or
approximately 180 ml of 40% alcohol [vodka] in an 80-kg male) but in some subjects, postural
dizziness and orthostatic hypotension were observed. The effect of alcohol on cognitive function was
not augmented by tadalafil (10 mg).
CYP1A2 substrates (e.g. theophylline)
When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase
inhibitor) there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small
(3.5 bpm) increase in heart rate.
CYP2C9 substrates (e.g.R-warfarin)
Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or
R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by
warfarin.
Aspirin
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic
acid.
5
P-glycoprotein substrates (e.g. digoxin)
Tadalafil (40 mg once per day) had no clinically significant effect on the pharmacokinetics of digoxin.
Oral Contraceptive Pill
At steady-state, tadalafil (40 mg once per day) increased ethinylestradiol exposure (AUC) by 26% and
C
max
by 70% relative to oral contraceptive administered with placebo. There was no statistically
significant effect of tadalafil on levonorgestrel which suggests the effect of ethinylestradiol is due to
inhibition of gut sulphation by tadalafil. The clinical relevance of this finding is uncertain.
Terbutaline
A similar increase in AUC and C
max
seen with ethinylestradiol may be expected with oral
administration of terbutaline, probably due to inhibition of gut sulphation by tadalafil. The clinical
relevance of this finding is uncertain
There are limited data from the use of tadalafil in pregnant women. Animal studies do not indicate
direct or indirect harmful effects with respect to pregnancy
,
embryonal/foetal development, parturition
or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the
use of ADCIRCA during pregnancy.
Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A
risk to the suckling child cannot be excluded. ADCIRCA should not be used during breast feeding.
No studies on the effect on the ability to drive and use machines have been performed. Although the
frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients
should be aware of how they react to ADCIRCA, before driving or operating machinery.
a.
Summary of the safety profile
The most commonly reported adverse reactions, occurring in ≥ 10% of subjects in the tadalafil 40-mg
treatment arm, were headache, nausea, back pain, dyspepsia, flushing, myalgia, nasopharingitis and
pain in extremity. The adverse reactions reported were transient, and generally mild or moderate.
Adverse reaction data are limited in patients over 75 years of age.
b.
Tabulated summary of adverse reactions
In the pivotal placebo-controlled study of ADCIRCA for the treatment of PAH, a total of 323 patients
were treated with ADCIRCA at doses ranging from 2.5 mg to 40 mg once daily and 82 patients were
treated with placebo. The duration of treatment was 16 weeks. The overall frequency of
discontinuation due to adverse events was low (ADCIRCA 11%, placebo 16%). Three hundred and
fifty seven (357) subjects who completed the pivotal study entered a long-term extension study.
Doses studied were 20 mg and 40 mg once daily.
The table below lists the adverse reactions reported during the placebo-controlled clinical trial in
patients with PAH treated with ADCIRCA. Also included in the table are some adverse
events/reactions which have been reported in clinical trials and/or post marketing with tadalafil in the
treatment of male erectile dysfunction. These events have either been assigned a frequency of “Not
known,” as the frequency in PAH patients cannot be estimated from the available data or assigned a
frequency based on the clinical trial data from the pivotal placebo-controlled study of ADCIRCA.
Adverse reactions
6
Frequency estimate: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to
<1/100), Rare (≥1/10,000 to <1/1000), Very Rare (<1/10,000) and Not known (cannot be estimated
from the available data).
Very common
(≥1/10)
Common
(≥1/100 to <1/10)
Uncommon
(
≥
1/1000 to
<
1/100)
Rare
(
≥
1/10,000 to
<
1/1000)
Not known
1
Immune system disorders
Hypersensitivity
reactions
5
Nervous System disorders
Headache
7
Migraine
5
Seizures
5
,
Transient
amnesia
5
Stroke
2
(including
haemorrhagic
events)
Eye disorders
Blurred vision
Non-arteritic
anterior ischemic
optic neuropathy
(NAION),
Retinal vascular
occlusion, Visual
field defect
Ear and labyrinth disorders
Sudden hearing
loss
6
Cardiac disorders
Chest pain
2
,
Palpitations
2, 5
Sudden cardiac
death
2, 5
,
Tachycardia
2, 5
Unstable angina
pectoris,
Ventricular
arrhythmia,
Myocardial
Infarction
2
Vascular disorders
Flushing
Hypotension
Hypertension
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis
(including nasal
congestion, sinus
congestion and
rhinitis)
Epistaxis
Gastrointestinal disorders
Nausea,
Dyspepsia
(including
abdominal
pain/discomfort
3
)
Vomiting,
Gastroesophageal
reflux
Skin and subcutaneous tissue disorders
Rash
Urticaria
5
,
Hyperhydrosis
(sweating)
5
Stevens-Johnson
Syndrome,
Exfoliative
dermatitis
Musculoskeletal, connective tissue and bone disorders
Myalgia,
Back pain
7
Pain in extremity
(including limb
discomfort)
Reproductive system and breast disorders
Increased uterine
bleeding
4
Priapism
5
Prolonged
erections
General disorders and administration site conditions
Facial oedema,
Chest pain
2
(1) Events not reported in registration trials and cannot be estimated from the available data. The
adverse reactions have been included in the table as a result of postmarketing or clinical trial data from
the use of tadalafil in the treatment of erectile dysfunction.
(2) Most of the patients in whom these events have been reported had pre-existing cardiovascular risk
factors.
(3) Actual MedDRA terms included are abdominal discomfort, abdominal pain, abdominal pain lower,
abdominal pain upper, and stomach discomfort.
(4) Clinical non-MedDRA term to include reports of abnormal/excessive menstrual bleeding
conditions such as menorrhagia, metrorrhagia, menometrorrhagia, or vaginal hemorrhage.
(5) The adverse reactions have been included in the table as a result of postmarketing or clinical trial
data from the use of tadalafil in the treatment of erectile dysfunction; and in addition, the frequency
estimates are based on only 1 or 2 patients experiencing the adverse reaction in the pivotal placebo-
controlled study of ADCIRCA.
(6) Sudden decrease or loss of hearing has been reported in a small number of postmarketing and
clinical trial cases with the use of all PDE5 inhibitors, including tadalafil.
(7) See section c)
c.
Description of selected adverse reactions
Headache was the most commonly reported adverse reaction. Headache may occur at the beginning of
therapy; and decreases over time even if treatment is continued.
Single doses of up to 500 mg have been given to healthy subjects, and multiple daily doses up to
100 mg have been given to patients with erectile dysfunction. Adverse events were similar to those
seen at lower doses.
In cases of overdose, standard supportive measures should be adopted as required. Haemodialysis
contributes negligibly to tadalafil elimination.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in erectile dysfunction, ATC Code G04BE08.
Mechanism of action
Tadalafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), the enzyme
responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial
hypertension is associated with impaired release of nitric oxide by the vascular endothelium and
consequent reduction of cGMP concentrations within the pulmonary vascular smooth muscle. PDE5
is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil
increases the concentrations of cGMP resulting in relaxation of the pulmonary vascular smooth muscle
cell and vasodilation of the pulmonary vascular bed.
8
Pharmacodynamic effects
Studies
in vitro
have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in
corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets,
kidney, lung, and cerebellum. The effect of tadalafil is more potent on PDE5 than on other
phosphodiesterases. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE1, PDE2, and
PDE4, enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is
> 10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels.
This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac
contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6,
an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also
> 10,000-fold more potent for PDE5 than for PDE7 through PDE10.
Efficacy in patients with pulmonary arterial hypertension (PAH)
A randomised, double-blind, placebo-controlled study was conducted in 405 patients with pulmonary
arterial hypertension. Allowed background therapy included bosentan (stable maintenance dose up to
125 mg twice daily) and chronic anticoagulation, digoxin, diuretics and oxygen. More than half
(53.3%) of the subjects in the study were receiving concomitant bosentan therapy.
Patients were randomised to one of five treatment groups (tadalafil 2.5 mg, 10 mg, 20 mg, 40 mg, or
placebo). Subjects were at least 12 years of age and had a diagnosis of PAH that was idiopathic,
related to collagen disease, related to anorexigen use, related to human immunodeficiency virus (HIV)
infection, associated with an atrial-septal defect, or associated with surgical repair of at least 1 year in
duration of a congenital systemic-to-pulmonary shunt (for example, ventricular septal defect, patent
ductus arteriosus). The mean age of all subjects was 54 years (range 14 to 90 years) with the majority
of subjects being Caucasian (80.5%) and female (78.3%). Pulmonary arterial hypertension (PAH)
etiologies were predominantly idiopathic PAH (61.0%) and related to collagen vascular disease
(23.5%). The majority of subjects had a World Health Organization (WHO) Functional Class III
(65.2%) or II (32.1%). The mean baseline 6-minute-walk-distance (6MWD) was 343.6 meters.
The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance
(6MWD). Only tadalafil 40 mg achieved the protocol defined level of significance with a placebo-
adjusted median increase in 6MWD of 26 metres (p=0.0004; 95% CI: 9.5, 44.0; Pre-specified Hodges-
Lehman method) (mean 33 metres, 95% CI: 15.2, 50.3). The improvement in walk distance was
apparent from 8 weeks of treatment. Significant improvement (p<0.01) in the 6MWD was
demonstrated at week 12 when the subjects were asked to delay taking study medication in order to
reflect trough drug concentration. Results were generally consistent in subgroups according to age,
gender, PAH aetiology and baseline WHO functional class and 6MWD. The placebo-adjusted median
increase in 6MWD was 17 metres (p=0.09; 95% CI: : -7.1, 43.0; Pre-specified Hodges-Lehman
method) (mean 23 metres, 95% CI; -2.4, 47.8) in those patients who received tadalafil 40 mg in
addition to their concomitant bosentan (n=39), and was 39 metres (p<0.01, 95% CI:13.0, 66.0; Pre-
specified Hodges-Lehman method) (mean 44 metres, 95% CI: 19.7, 69.0) in those patients who
received tadalafil 40 mg alone (n=37).
The proportion of patients with improvement in WHO functional class by week 16 was similar in the
tadalafil 40 mg and placebo groups (23% vs. 21%).
The incidence of clinical worsening by week 16
in patients treated with tadalafil 40 mg (5%; 4 of 79 patients) was less than placebo (16%; 13 of 82
patients). Changes in the Borg dyspnoea score were small and non-significant with both placebo and
tadalafil 40 mg.
Additionally, improvements compared to placebo were observed with tadalafil 40 mg in the physical
functioning, role-physical, bodily pain, general health, vitality and social functioning domains of the
SF-36. No improvements were observed in the role emotional and mental health domains of the SF-36.
Improvements compared to placebo were observed with tadalafil 40 mg in the EuroQol (EQ-5D) US
and UK index scores comprising mobility, self-care, usual activities, pain/discomfort,
anxiety/depression components, and in the visual analogue scale (VAS).
9
Cardiopulmonary hemodynamics was performed in 93 patients. Tadalafil 40mg increased cardiac
output (0.6 L/min) and reduced pulmonary artery pressures (-4.3mmHg) and pulmonary vascular
resistance (-209dyn.s/cm
5
) compared to baseline (p<0.05). However, post hoc analyses demonstrated
that changes from baseline in cardiopulmonary hemodynamic parameters for the tadalafil 40 mg
treatment group were not significantly different compared to placebo.
Long-term treatment
357 patients from the placebo-controlled study entered a long-term extension study. Of these, 311
patients had been treated with tadalafil for at least 6 months and 293 for 1 year (median exposure 365
days; range 2 days to 415 days). For those patients for which there are data, the survival rate at 1 year
is 96.4%
.
Additionally, 6 minute walk distance and WHO functional class status appeared to be stable
in those treated with tadalafil for 1 year.
Tadalafil 20 mg administered to healthy subjects produced no significant difference compared to
placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg,
respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of
0.2/4.6 mm Hg, respectively), and no significant change in heart rate.
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination
(blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with
the low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of
changes in colour vision were rare (< 0.1 %).
Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil
10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. In
two of these studies decreases were observed in sperm count and concentration related to tadalafil
treatment of unlikely clinical relevance. These effects were not associated with changes in other
parameters such as motility, morphology and FSH.
5.2 Pharmacokinetic properties
Absorption
Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma
concentration (C
max
) is achieved at a median time of 4 hours after dosing. Absolute bioavailability of
tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food, thus ADCIRCA may be taken
with or without food. The time of dosing (morning versus evening after a single 10 mg administration)
had no clinically relevant effects on the rate and extent of absorption.
Distribution
The mean volume of distribution is approximately 77 l at steady state, indicating that tadalafil is
distributed into tissues. At therapeutic concentrations, 94 % of tadalafil in plasma is bound to proteins.
Protein binding is not affected by impaired renal function.
Less than 0.0005 % of the administered dose appeared in the semen of healthy subjects.
Biotransformation
Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major
circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less
potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed
metabolite concentrations.
Elimination
The mean oral clearance for tadalafil is 3.4 l/h at steady state and the mean terminal half-life is 16
hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites, mainly in the
faeces (approximately 61 % of the dose) and to a lesser extent in the urine (approximately 36 % of the
dose).
10
Linearity/non-linearity
Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in
healthy subjects. Between 20 mg to 40 mg, a less than proportional increase in exposure is observed.
During tadalafil 20 mg and 40 mg once daily dosing, steady-state plasma concentrations are attained
within 5 days, and exposure is approximately 1.5 fold of that after a single dose.
Population pharmacokinetics
In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil
exposure at steady-state following 40 mg was 26% higher when compared to those of healthy
volunteers. There were no clinically relevant differences in C
max
compared to healthy volunteers. The
results suggest a lower clearance of tadalafil in patients with pulmonary hypertension compared to
healthy volunteers.
Special Populations
Elderly
Healthy elderly subjects (65 years or over), had a lower oral clearance of tadalafil, resulting in 25 %
higher exposure (AUC) relative to healthy subjects aged 19 to 45 years after a 10 mg dose. This effect
of age is not clinically significant and does not warrant a dose adjustment.
Renal insufficiency
In clinical pharmacology studies using single-dose tadalafil (5-20 mg), tadalafil exposure (AUC)
approximately doubled in subjects with mild (creatinine clearance 51 to 80 ml/min) or moderate
(creatinine clearance 31 to 50 ml/min) renal impairment and in subjects with end-stage renal disease
on dialysis. In haemodialysis patients, C
max
was 41% higher than that observed in healthy subjects.
Haemodialysis contributes negligibly to tadalafil elimination.
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to
influence clearance by dialysis, tadalafil is not recommended in patients with severe renal impairment.
Hepatic insufficiency
Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh Class
A and B) is comparable to exposure in healthy subjects when a dose of 10 mg is administered. If
tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the
prescribing physician. There are no available data about the administration of doses higher than 10 mg
of tadalafil to patients with hepatic impairment.
Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing
of tadalafil in these patients is not recommended .
Patients with diabetes
Tadalafil exposure (AUC) in patients with diabetes was approximately 19 % lower than the AUC
value for healthy subjects after a 10 mg dose. This difference in exposure does not warrant a dose
adjustment.
Race
Pharmacokinetic studies have included subjects and patients from different ethnic groups, and no
differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted.
Gender
In healthy female and male subjects following single and multiple-doses of tadalafil, no clinically
relevant differences in exposure were observed. No dose adjustment is warranted.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to
reproduction.
11
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received
up to 1000 mg/kg/day tadalafil. In a rat pre- and postnatal development study, the no observed effect
dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was
approximately 18 times the human AUC at a 20 mg dose.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12
months at doses of 25 mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7 – 18.6] than
seen in humans given a single 20 mg dose) and above, there was regression of the seminiferous tubular
epithelium that resulted in a decrease in spermatogenesis in some dogs. See also section 5.1.
6.
6.1 List of excipients
Tablet core:
lactose monohydrate,
croscarmellose sodium,
hydroxypropylcellulose,
microcrystalline cellulose,
sodium laurilsulfate,
magnesium stearate.
Film-coat:
lactose monohydrate,
hypromellose,
triacetin,
titanium dioxide (E171),
iron oxide yellow (E172),
iron oxide red (E172),
talc.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect from moisture. Do not store above 30°C.
6.5 Nature and contents of container
Aluminium/PVC/PE/PCTFE blisters in cartons of 28 and 56 film-coated tablets.
Not all packs sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
12
Eli Lilly Nederland B.V.
Grootslag 1-5, NL-3991 RA, Houten
The Netherlands
8.
EU/1/08/476/005-006
9.
Date of first authorisation: 1 October 2008
13
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
14
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Lilly S.A.
Avda de la Industria 30
E-28010 Alcobendas (Madrid)
Spain
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 2.2 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.3 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by
the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON TEXT
1.
ADCIRCA 20 mg film-coated tablets
tadalafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 20 mg tadalafil
3.
LIST OF EXCIPIENTS
lactose monohydrate
See leaflet for further information.
4.
28 film-coated tablets
56 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use. Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Store in the original package in order to protect from moisture. Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
18
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Eli Lilly Nederland B.V.
Grootslag 1-5, NL-3991 RA, Houten
The Netherlands
EU/1/08/476/005-006
13. BATCH NUMBER
Lot.
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
ADCIRCA 20 mg
19
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
ADCIRCA 20 mg tablets
tadalafil
2.
Lilly
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot.
5.
OTHER
Mon, Tue, Wed, Thu, Fri, Sat, Sun.
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET : INFORMATION FOR THE USER
ADCIRCA 20 mg film-coated tablets
tadalafil
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What ADCIRCA is and what it is used for
2.
Before you take ADCIRCA
3.
How to take ADCIRCA
5
How to store ADCIRCA
6.
Further information
1.
WHAT ADCIRCA IS AND WHAT IT IS USED FOR
ADCIRCA is a treatment for pulmonary arterial hypertension.
ADCIRCA belongs to a group of medicines called phosphodiesterase type 5 (PDE5) inhibitors which
work by helping the blood vessels around your lungs relax, improving the flow of blood into your
lungs. The result of this is an improved ability to do physical activity.
2.
BEFORE YOU TAKE ADCIRCA
Do NOT take ADCIRCA if you:
- are allergic (hypersensitive) to tadalafil or any of the other ingredients (see Section 6 and end of
Section 2).
- are taking any form of nitrates such as amyl nitrite, used in the treatment of chest pain. ADCIRCA
has been shown to increase the effects of these medicines. If you are taking any form of nitrate or
are unsure tell your doctor.
-
have ever had loss of vision – a condition described as “stroke of the eye” (non-arteritic anterior
ischemic optic neuropathy - NAION).
-
have had a heart attack in the last 3 months
-
have low blood pressure
ADCIRCA is not intended for use by children and adolescents under the age of 18.
Take special care with ADCIRCA
Before taking the tablets, tell your doctor if you have:
- any heart problems other than your pulmonary hypertension
-
problems with your blood pressure
-
any hereditary eye disease
-
an abnormality of red blood cells (sickle cell anaemia)
-
cancer of the bone marrow (multiple myeloma)
22
-
If you have any further questions, ask your doctor or pharmacist.
4.
Possible side effects
-
cancer of the blood cells (leukaemia)
-
any deformation of your penis, or unwanted or persistent erections lasting more than 4 hours
-
a serious liver problem
-
a severe kidney problem.
If you experience sudden decrease or loss of vision, contact your doctor immediately.
Taking other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including those
obtained without prescription.
Do NOT take these tablets if you are already taking nitrates .
Some medicines may be affected by ADCIRCA or they may affect how well ADCIRCA will work.
Tell your doctor or pharmacist if you are already taking:
- bosentan (another treatment for pulmonary aterial hypertension)
- nitrates (for chest pain)
- alpha blockers used to treat high blood pressure or prostate problems.
- rifampicin (to treat bacterial infections)
- ketoconazole tablets (to treat fungal infections)
- ritonavir (for HIV treatment)
- tablets for erectile dysfunction (PDE5 inhibitors).
Taking ADCIRCA with food and drink
These tablets can be taken with or without food.
Drinking alcohol may temporarily lower your blood pressure. If you have taken or are planning to take
ADCIRCA, avoid excessive drinking (blood alcohol level of 0.08% or greater), since this may
increase the risk of dizziness when standing up.
Pregnancy and breastfeeding
If you are pregnant, or think you might be pregnant, tell your doctor as soon as possible. Do not take
ADCIRCA when pregnant, unless it is strictly necessary and you have discussed this with your doctor.
Do not breastfeed while taking these tablets as it is not known if the medicine passes into human
breast milk. Ask your doctor or pharmacist for advice before taking any medicine while pregnant or
breastfeeding.
Driving and using machines
Dizziness has been reported. Check carefully how you react to the medicines before driving or using
any machinery.
Important information about some of the ingredients of ADCIRCA:
Lactose – if you know you have an intolerance to some sugars, contact your doctor before taking this
medicinal product.
3.
HOW TO TAKE ADCIRCA
Always take ADCIRCA exactly as your doctor has told you. You should check with him/her if you are
unsure.
ADCIRCA is supplied as a 20 mg tablet.
The usual dose
is two 20 mg tablets taken once a day. You
should take both tablets at the same time, one after the other. If you have a mild or moderate liver or
kidney problem, your doctor may advise you to take only one 20 mg tablet per day.
Swallow the tablets whole with a drink of water. The tablets can be taken with or without food.
23
If you take more ADCIRCA than you should
If you or anyone else takes more tablets than they should, tell your doctor or go to a hospital
immediately, taking the medicine or pack with you.
If you forget to take ADCIRCA
Take your dose as soon as you remember but do NOT take a double dose to make up for the one that
you have forgotten.
If you stop taking ADCIRCA
Do not stop taking your tablets, unless advised otherwise by your doctor.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, ADCIRCA can cause side effects, although not everybody gets them. These effects
are normally mild to moderate in nature.
The following side effects have been reported:
Very common
(seen in more than 1 in every 10 patients)
-
headache, flushing, nasal and sinus congestion (blocked nose), nausea, indigestion (including
abdominal pain or discomfort), muscle aches, back pain and pain in the extremity (including limb
discomfort).
Common
(seen in 1 to 10 in every 100 patients)
-
blurred vision, low blood pressure, nosebleed, vomiting, increased or abnormal uterine bleeding,
allergic reactions (including skin rashes), swelling of the face, acid reflux, migraine, chest pain
and irregular heartbeat.
Uncommon
(seen in 1 to 10 in every 1000 patients)
-
seizures, passing memory loss, hives, excessive sweating, prolonged and possibly painful erection,
high blood pressure, fast heart rate and sudden cardiac death.
PDE5 inhibitors
are also used for the treatment of erectile dysfunction in men. Some side effects have
been rarely reported:
-
Partial, sudden, temporary or permanent decrease or loss of vision in one or both eyes. Sudden
decrease or loss of hearing has also been reported.
Some side effects have been reported in men taking tadalafil for the treatment of erectile dysfunction.
These events were not seen in clinical trials for pulmonary arterial hypertension and therefore
frequency is unknown:
-
swelling of the eyelids, eye pain, red eyes, heart attack and stroke.
Most but not all of those men reporting fast heart rate, irregular heartbeat, heart attack, stroke and
sudden cardiac death had known heart problems before taking tadalafil. It is not possible to determine
whether these events were related directly to tadalafil.
Effects were seen in one animal species that might indicate impairment of fertility in men. Subsequent
studies in man suggest that this effect is unlikely; however a decrease in sperm concentration was seen
in some men.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
24
5.
HOW TO STORE ADCIRCA
Keep out of the reach and sight of children.
Do not use ADCIRCA after the expiry date stated on the carton and blister.
Store in the original package in order to protect from moisture. Do not store above 30°C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What ADCIRCA contains
The active substance is tadalafil. Each tablet contains 20 mg of tadalafil.
The other ingredients are:
Tablet core: lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, microcrystalline
cellulose, sodium laurilsulfate, magnesium stearate.
Film-coat: lactose monohydrate, hypromellose, triacetin, titanium dioxide (E171), iron oxide yellow
(E172), iron oxide red (E172), talc.
What ADCIRCA looks like and contents of the pack
ADCIRCA 20 mg comes as orange film-coated tablets. They are in the shape of almonds and have
"4467" marked on one side.
ADCIRCA 20 mg is available in blister packs containing 28 or 56 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Eli Lilly Nederland B.V.,
Grootslag 1-5, NL-3991 RA, Houten, The
Netherlands
Manufacturer: Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
Belgique/België/Belgien
Eli Lilly Benelux S.A/N.V.
Tél/Tel: +32-(0) 2 548 84 84
Luxembourg/Luxemburg
Eli Lilly Benelux S.A/N.V.
Tél/Tel: +32-(0)2 548 84 84
България
ТП "Ели Лили Недерланд" Б.В. - България
тел. + 359 2 491 41 40
Magyarország
Lilly Hungária Kft
Tel: + 36 1 328 5100
Česká republika
ELI LILLY ČR, s.r.o.
Tel: + 420 234 664 111
Malta
Charles de Giorgio Ltd.
Tel: + 356 25600 500
Danmark
Eli Lilly Danmark A/S
Tlf: +45 45 26 60 00
Nederland
Eli Lilly Nederland B.V.
Tel: + 31-(0) 30 60 25 800
Deutschland
Lilly Deutschland GmbH
Tel. + 49-(0) 6172 273 2222
Norge
Eli Lilly Norge A.S.
Tlf: + 47 22 88 18 00
Eesti
Eli Lilly Holdings Limited. Eesti filiaal
Tel:
+
372 6441100
Österreich
Eli Lilly Ges.m.b.H.
Tel: +43-(0) 1 711 780
Ελλάδα
Polska
25
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε
Τηλ: +30 210 629 4600
Eli Lilly Polska Sp. z o.o.
Tel.: +48 (0) 22 440 33 00
España
Lilly, S.A.
Tel: + 34 91 663 5000
Portugal
Lilly Portugal
Produtos Farmacêuticos, Lda.
Tel: +351-21-4126600
France
Lilly France S.A.S
Tél.: +33-(0)1 55 49 34 34
România
Eli Lilly România S.R.L.
Tel: + 40 21 4023000
Ireland
Eli Lilly and Company (Ireland) Limited.
Tel: +353-(0) 1 661 4377
Slovenija
Eli Lilly farmacevtska družba, d.o.o
.
Tel: +386 (0)1 580 00 10
Ísland
Icepharma hf.
Simi: + 354 540 8000
Slovenská republika
Eli Lilly Slovakia, s.r.o.
Tel: + 421 220 663 111
Italia
Eli Lilly Italia S.p.A.
Tel: + 39- 055 42571
Suomi/Finland
Oy Eli Lilly Finland Ab.
Puh/Tel: + 358-(0) 9 85 45 250
Κύπρος
Phadisco Ltd
Τηλ: +357 22 715000
Sverige
Eli Lilly Sweden AB
Tel: +46 (0) 8 737 88 00
Latvija
Eli Lilly Holdings Limited
pārstāvniecība Latvijā
Tel:
+
371 67364000
United Kingdom
Eli Lilly and Company Limited
Tel: +44-(0) 1256 315000
Lietuva
Eli Lilly Holdings Limited atstovybė
Tel. +370 (5) 2649600
This leaflet was last approved in {date}
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu
26
Source: European Medicines Agency
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