ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
CIALIS 2.5 mg film-coated tablets
2.
Each tablet contains 2.5 mg tadalafil.
Excipients: Each coated tablet contains 92 mg of lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Light orange-yellow and almond shaped tablets, marked "C 2 ½" on one side.
4.
Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective, sexual stimulation is required.
CIALIS is not indicated for use by women.
Method of administration
CIALIS is available as 2.5, 5, 10, and 20 mg film-coated tablets for oral use.
Posology
Use in adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or
without food.
In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It
may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not
recommended for continuous daily use.
In patients who anticipate a frequent use of CIALIS (i.e., at least twice weekly) a once daily regimen
with the lowest doses of CIALIS might be considered suitable, based on patient choice and the
physician’s judgement.
In these patients the recommended dose is 5 mg taken once a day at approximately the same time of
day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.
Use in elderly men
2
Dose adjustments are not required in elderly patients.
Use in men with impaired renal function
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients
with severe renal impairment 10 mg is the maximum recommended dose. Once-a-day dosing of
tadalafil is not recommended in patients with severe renal impairment.(See sections 4.4 and 5.2).
Use in men with impaired hepatic function
The recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and with or
without food. There is limited clinical data on the safety of CIALIS in patients with severe hepatic
impairment (Child-Pugh Class C); if 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. Once-a-day dosing has not been
evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk
evaluation should be undertaken by the prescribing physician. (See section 5.2).
Use in men with diabetes
Dose adjustments are not required in diabetic patients.
Paediatric population
CIALIS should not be used in individuals below 18 years of age.
Hypersensitivity to the active substance or to any of the excipients.
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 CIALIS to patients who are using any form of organic nitrate is
contraindicated. (See section 4.5).
Agents for the treatment of erectile dysfunction, including CIALIS, must not be used in men with
cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential
cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.
The following groups of patients with cardiovascular disease were not included in clinical trials and
the use of tadalafil is therefore contraindicated:
-
patients with myocardial infarction within the last 90 days,
-
patients with unstable angina or angina occurring during sexual intercourse,
-
patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,
-
patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), or uncontrolled
hypertension,
-
patients with a stroke within the last 6 months.
CIALIS 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).
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and
determine potential underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular
status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil
has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1)
and as such potentiate the hypotensive effect of nitrates (see section 4.3).
3
In patients receiving concomitant antihypertensive medicines, tadalafil may induce a blood pressure
decrease. When initiating daily treatment with tadalafil, appropriate clinical considerations should be
given to a possible dose adjustment of the antihypertensive therapy.
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina
pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and
tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in
whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not
possible to definitively determine whether these events are related directly to these risk factors, to
CIALIS, to sexual activity, or to a combination of these or other factors.
Visual defects and cases of NAION have been reported in connection with the intake of CIALIS and
other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should
stop taking CIALIS and consult a physician immediately (see section 4.3).
Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to
influence clearance by dialysis, once-a-day dosing of CIALIS is not recommended in patients with
severe renal impairment.
There is limited clinical data on the safety of single-dose administration of CIALIS in patients with
severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration has not been evaluated
in patients with hepatic insufficiency. If CIALIS is prescribed, a careful individual benefit/risk
evaluation should be undertaken by the prescribing physician.
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.
Agents for the treatment of erectile dysfunction, including CIALIS, 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).
The evaluation of erectile dysfunction should include a determination of potential underlying causes
and the identification of appropriate treatment following an appropriate medical assessment. It is not
known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-nerve-
sparing prostatectomy.
In patients who are taking alpha
1
blockers concomitant administration of CIALIS may lead to
symptomatic hypotension in some patients (see section 4.5). The combination of tadalafil and
doxazosin is not recommended.
Caution should be exercised when prescribing CIALIS to patients using potent CYP3A4 inhibitors
(ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin) as increased tadalafil exposure
(AUC) has been observed if the medicines are combined (see section 4.5).
The safety and efficacy of combinations of CIALIS and other PDE5 inhibitors or other treatments for
erectile dysfunction have not been studied. The patients should be informed not to take CIALIS with
such combinations.
CIALIS 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.
4
Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard
to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant
interactions at higher doses cannot be completely ruled out.
Effects of other substances on tadalafil
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole
(200 mg daily), increased tadalafil (10 mg) 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)
exposure (AUC) 4-fold and C
max
by 22%. Ritonavir, a protease inhibitor (200 mg twice daily), which
is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg)
exposure (AUC) 2-fold with no change in C
max
. Although specific interactions have not been studied,
other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin,
clarithromycin, itraconazole and grapefruit juice should be co-administered with caution as they would
be expected to increase plasma concentrations of tadalafil (see section 4.4)
Consequently the incidence of the undesirable effects listed in section 4.8 might be increased.
The role of transporters (for example p-glycoprotein) in the disposition of tadalafil is not known.
There is thus the potential of drug interactions mediated by inhibition of transporters.
A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values for
tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil;
the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4 such as phenobarbital,
phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of tadalafil on other medicinal products
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of
nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is
contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects
receiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various
times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had
elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of CIALIS (2.5 mg-20 mg),
where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48
hours should have elapsed after the last dose of CIALIS before nitrate administration is considered. In
such circumstances, nitrates should only be administered under close medical supervision with
appropriate haemodynamic monitoring.
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. However, caution should be exercised when using tadalafil in
patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at
minimal dosage and progressively adjusted.
In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of
antihypertensive agents was examined. Major classes of antihypertensive agents were studied,
including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors
(enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and
angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides,
calcium channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10 mg except for studies
with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no
clinically significant interaction with any of these classes. In another clinical pharmacology study
5
tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In subjects
taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the
degree of blood-pressure control. In this regard, study subjects whose blood pressure was well
controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects
whose blood pressure was not controlled, the reduction was greater although this reduction was not
associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant
antihypertensive medicines, tadalafil 20 mg may induce a blood pressure decrease, which (with the
exception of alpha blockers -see above-) is, in general, minor and not likely to be clinically relevant.
Analysis of phase 3 clinical trial data showed no difference in adverse events in patients taking
tadalafil with or without antihypertensive medicines. However, appropriate clinical advice should be
given to patients regarding a possible decrease in blood pressure when they are treated with
antihypertensive medicines.
When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase
inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only
pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor
and was of no clinical significance in this study, it should be considered when co-administering these
medicines.
Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a
similar increase may be expected with oral administration of terbutaline, although the clinical
consequence of this is uncertain.
Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co-
administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations
were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to
maximize the rate of alcohol absorption (overnight fast with no food until 2 hours after 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. When tadalafil was administered with lower
doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar
frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil
(10 mg).
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of
medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not
inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and
CYP2C19.
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.
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic
acid.
Specific interaction studies with antidiabetic agents were not conducted.
CIALIS is not indicated for use by women.
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 CIALIS during pregnancy.
6
Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A
risk to the suckling child cannot be excluded. CIALIS 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 CIALIS, before driving or operating machinery.
a.
Summary of the safety profile
The most commonly reported adverse reactions were headache and dyspepsia. 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
The table below lists the adverse reactions reported in erectile dysfunction placebo-controlled clinical
trials in patients treated with CIALIS on demand and daily dosing with doses within the currently
approved dosing range for CIALIS. Adverse reactions are also included that have been reported from
postmarketing surveillance in patients taking CIALIS.
Adverse reactions
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 (events not reported in
registration trials cannot be estimated from postmarketing spontaneous reports).
Very common
(≥1/10)
Common
(≥1/100 to <1/10)
Uncommon
(
≥
1/1000 to
<
1/100)
Rare
(
≥
1/10,000 to
<
1/1000)
Immune system disorders
Hypersensitivity
reactions
Nervous System disorders
Headache
Dizziness
Stroke
1
(including
haemorrhagic
events), Syncope,
Transient
ischaemic
attacks
1
,
Migraine
3
,
Seizures,
Transient
amnesia
Eye disorders
Blurred vision,
Sensations
described as eye
pain
Visual field
defect, Swelling
of eyelids,
Conjunctival
hyperaemia,
Non-arteritic
anterior ischemic
optic neuropathy
(NAION)
3
,
Retinal vascular
7
occlusion
3
Ear and labyrinth disorders
Cardiac disorders
1
Sudden hearing
loss
2
Tachycardia,
Palpitations
Myocardial
infarction,
Unstable angina
pectoris
3
,
Ventricular
arrhythmia
3
Vascular disorders
Flushing
Hypotension
(more commonly
reported when
tadalafil is given
to patients who
are already
taking
antihypertensive
agents),
Hypertension
Respiratory, thoracic and mediastinal disorders
Nasal congestion
Epistaxis
Gastrointestinal disorders
Dyspepsia,
Abdominal pain,
Gastro-
oesophageal
reflux
Skin and subcutaneous tissue disorders
Rash,
Hyperhydrosis
(sweating)
Urticaria,
Stevens-Johnson
syndrome
3
,
Exfoliative
dermatitis
3
,
Musculoskeletal, connective tissue and bone disorders
Back pain,
Myalgia
Reproductive system and breast disorders
Prolonged
erections,
Priapism
3
General disorders and administration site conditions
Chest pain
1
Facial oedema
3
,
Sudden cardiac
death
1, 3
(1) Most of the patients in whom these events have been reported had pre-existing cardiovascular risk
factors (see section 4.4).
(2) 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.
(3) Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical
trials
c.
Description of selected adverse reactions
8
A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in
patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities
were not associated with adverse reactions.
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. 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 selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific
phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide,
inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This
results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an
erection. Tadalafil has no effect in the absence of sexual stimulation.
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.
Clinical efficacy and safety
Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of
responsiveness to CIALIS on demand. Tadalafil demonstrated statistically significant improvement in
erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing,
as well as patients’ ability to attain and maintain erections for successful intercourse compared to
placebo as early as 16 minutes following dosing.
Tadalafil 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 CIALIS
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
9
treatment of unlikely clinical relevance. These effects were not associated with changes in other
parameters such as motility, morphology and FSH.
Tadalafil at doses of 2.5, 5, and 10 mg taken once a day was initially evaluated in 3 clinical studies
involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile dysfunction of
various severities (mild, moderate, severe) and etiologies. In the two primary efficacy studies of
general populations, the mean per-subject proportion of successful intercourse attempts were 57 and
67% on CIALIS 5mg, 50% on CIALIS 2.5mg as compared to 31 and 37% with placebo. In the study
in patients with erectile dysfunction secondary to diabetes, the mean per-subject proportion of
successful attempts were 41 and 46% on CIALIS 5mg and 2.5mg, respectively, as compared to 28%
with placebo. Most patients in these three studies were responders to previous on-demand treatment
with PDE5 inhibitors. In a subsequent study, 217 patients who were treatment-naive to PDE5
inhibitors were randomized to CIALIS 5mg once a day vs. placebo. The mean per-subject proportion
of successful sexual intercourse attempts was 68% for CIALIS patients compared to 52% for patients
on placebo.
In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction
secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean
per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-
dose, on demand) of 48% as compared to 17% with placebo.
10
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 2 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 CIALIS may be taken
with or without food. The time of dosing (morning versus evening) had no clinically relevant effects
on the rate and extent of absorption.
Distribution
The mean volume of distribution is approximately 63 l, 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 2.5 l/h and the mean half-life is 17.5 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).
Linearity/non-linearity
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose
range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma
concentrations are attained within 5 days of once-daily dosing.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction are
similar to pharmacokinetics in subjects without erectile dysfunction.
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. 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 mg-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.
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. There is
limited clinical data on the safety of CIALIS in patients with severe hepatic insufficiency (Child-Pugh
Class C). There are no available data about the administration of once-a-day dosing of tadalafil to
patients with hepatic impairment. If CIALIS is prescribed once-a-day, a careful individual benefit/risk
evaluation should be undertaken by the prescribing physician.
11
Patients with diabetes
Tadalafil exposure (AUC) in patients with diabetes was approximately 19 % lower than the AUC
value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
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.
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 film-coated tablets.
6.6 Special precautions for disposal
12
No special requirements.
7.
Eli Lilly Nederland B.V.
Grootslag 1-5, NL-3991 RA, Houten
The Netherlands
8.
EU/1/02/237/006
9.
Date of first authorisation: 12 November 2002
Date of last renewal: 12 November 2007
13
1.
CIALIS 5 mg film-coated tablets
2.
Each tablet contains 5 mg tadalafil.
Excipients: Each coated tablet contains 127 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Light yellow and almond shaped tablets, marked "C 5" on one side.
4.
Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective, sexual stimulation is required.
CIALIS is not indicated for use by women.
Method of administration
CIALIS is available as 2.5, 5, 10 and 20 mg film-coated tablets for oral use.
Posology
Use in adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or
without food.
In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It
may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not
recommended for continuous daily use.
In patients who anticipate a frequent use of CIALIS (i.e., at least twice weekly) a once daily regimen
with the lowest doses of CIALIS might be considered suitable, based on patient choice and the
physician’s judgement.
In these patients the recommended dose is 5 mg taken once a day at approximately the same time of
day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.
Use in elderly men
14
Dose adjustments are not required in elderly patients.
Use in men with impaired renal function
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients
with severe renal impairment 10 mg is the maximum recommended dose. Once-a-day dosing of
tadalafil is not recommended in patients with severe renal impairment.(See sections 4. 4 and 5.2).
Use in men with impaired hepatic function
The recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and with or
without food. There is limited clinical data on the safety of CIALIS in patients with severe hepatic
impairment (Child-Pugh Class C); if 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. Once-a-day dosing has not been
evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk
evaluation should be undertaken by the prescribing physician. (See section 5.2).
Use in men with diabetes
Dose adjustments are not required in diabetic patients.
Paediatric population
CIALIS should not be used in individuals below 18 years of age.
Hypersensitivity to the active substance or to any of the excipients.
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 CIALIS to patients who are using any form of organic nitrate is
contraindicated. (See section 4.5).
Agents for the treatment of erectile dysfunction, including CIALIS, must not be used in men with
cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential
cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.
The following groups of patients with cardiovascular disease were not included in clinical trials and
the use of tadalafil is therefore contraindicated:
-
patients with myocardial infarction within the last 90 days,
-
patients with unstable angina or angina occurring during sexual intercourse,
-
patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,
-
patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), or uncontrolled
hypertension,
-
patients with a stroke within the last 6 months.
CIALIS 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).
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and
determine potential underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular
status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil
has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1)
and as such potentiate the hypotensive effect of nitrates (see section 4.3).
15
In patients receiving concomitant antihypertensive medicines, tadalafil may induce a blood pressure
decrease. When initiating daily treatment with tadalafil, appropriate clinical considerations should be
given to a possible dose adjustment of the antihypertensive therapy.
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina
pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and
tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in
whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not
possible to definitively determine whether these events are related directly to these risk factors, to
CIALIS, to sexual activity, or to a combination of these or other factors.
Visual defects and cases of NAION have been reported in connection with the intake of CIALIS and
other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should
stop taking CIALIS and consult a physician immediately (see section 4.3).
Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to
influence clearance by dialysis, once-a-day dosing of CIALIS is not recommended in patients with
severe renal impairment.
There is limited clinical data on the safety of single-dose administration of CIALIS in patients with
severe hepatic insufficiency (Child-Pugh Class C). Once-a-day administration has not been evaluated
in patients with hepatic insufficiency. If CIALIS is prescribed, a careful individual benefit/risk
evaluation should be undertaken by the prescribing physician.
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.
Agents for the treatment of erectile dysfunction, including CIALIS, 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).
The evaluation of erectile dysfunction should include a determination of potential underlying causes
and the identification of appropriate treatment following an appropriate medical assessment. It is not
known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-nerve-
sparing prostatectomy.
In patients who are taking alpha
1
blockers concomitant administration of CIALIS may lead to
symptomatic hypotension in some patients (see section 4.5). The combination of tadalafil and
doxazosin is not recommended.
Caution should be exercised when prescribing CIALIS to patients using potent CYP3A4 inhibitors
(ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin) as increased tadalafil exposure
(AUC) has been observed if the medicines are combined (see section 4.5).
The safety and efficacy of combinations of CIALIS and other PDE5 inhibitors or other treatments for
erectile dysfunction have not been studied. The patients should be informed not to take CIALIS with
such combinations.
CIALIS 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.
16
Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard
to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant
interactions at higher doses cannot be completely ruled out.
Effects of other substances on tadalafil
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole
(200 mg daily), increased tadalafil (10 mg) 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)
exposure (AUC) 4-fold and C
max
by 22%. Ritonavir, a protease inhibitor (200 mg twice daily), which
is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg)
exposure (AUC) 2-fold with no change in C
max
. Although specific interactions have not been studied,
other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin,
clarithromycin, itraconazole and grapefruit juice should be co-administered with caution as they would
be expected to increase plasma concentrations of tadalafil (see section 4.4)
Consequently the incidence of the undesirable effects listed in section 4.8 might be increased.
The role of transporters (for example p-glycoprotein) in the disposition of tadalafil is not known.
There is thus the potential of drug interactions mediated by inhibition of transporters.
A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values for
tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil;
the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4 such as phenobarbital,
phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of tadalafil on other medicinal products
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of
nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is
contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects
receiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various
times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had
elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of CIALIS (2.5 mg-20 mg),
where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48
hours should have elapsed after the last dose of CIALIS before nitrate administration is considered. In
such circumstances, nitrates should only be administered under close medical supervision with
appropriate haemodynamic monitoring.
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. However, caution should be exercised when using tadalafil in
patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at
minimal dosage and progressively adjusted.
In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of
antihypertensive agents was examined. Major classes of antihypertensive agents were studied,
including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors
(enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and
angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides,
calcium channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10 mg except for studies
with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no
clinically significant interaction with any of these classes. In another clinical pharmacology study
17
tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In subjects
taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the
degree of blood-pressure control. In this regard, study subjects whose blood pressure was well
controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects
whose blood pressure was not controlled, the reduction was greater although this reduction was not
associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant
antihypertensive medicines, tadalafil 20 mg may induce a blood pressure decrease, which (with the
exception of alpha blockers -see above-) is, in general, minor and not likely to be clinically relevant.
Analysis of phase 3 clinical trial data showed no difference in adverse events in patients taking
tadalafil with or without antihypertensive medicines. However, appropriate clinical advice should be
given to patients regarding a possible decrease in blood pressure when they are treated with
antihypertensive medicines.
When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase
inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only
pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor
and was of no clinical significance in this study, it should be considered when co-administering these
medicines.
Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a
similar increase may be expected with oral administration of terbutaline, although the clinical
consequence of this is uncertain.
Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co-
administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations
were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to
maximize the rate of alcohol absorption (overnight fast with no food until 2 hours after 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. When tadalafil was administered with lower
doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar
frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil
(10 mg).
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of
medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not
inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and
CYP2C19.
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.
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic
acid.
Specific interaction studies with antidiabetic agents were not conducted.
CIALIS is not indicated for use by women.
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 CIALIS during pregnancy.
18
Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A
risk to the suckling child cannot be excluded. CIALIS 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 CIALIS, before driving or operating machinery.
a.
Summary of the safety profile
The most commonly reported adverse reactions were headache and dyspepsia. 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
The table below lists the adverse reactions reported in erectile dysfunction placebo-controlled clinical
trials in patients treated with CIALIS on demand and daily dosing with doses within the currently
approved dosing range for CIALIS. Adverse reactions are also included that have been reported from
postmarketing surveillance in patients taking CIALIS.
Adverse reactions
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 (events not reported in registration trials cannot be estimated postmarketing spontaneous
reports)
Very common
(≥1/10)
Common
(≥1/100 to <1/10)
Uncommon
(
≥
1/1000 to
<
1/100)
Rare
(
≥
1/10,000 to
<
1/1000)
Immune system disorders
Hypersensitivity
reactions
Nervous System disorders
Headache
Dizziness
Stroke
1
(including
haemorrhagic
events), Syncope,
Transient
ischaemic
attacks
1
,
Migraine
3
,
Seizures,
Transient
amnesia
Eye disorders
Blurred vision,
Sensations
described as eye
pain
Visual field
defect, Swelling
of eyelids,
Conjunctival
hyperaemia,
Non-arteritic
anterior ischemic
optic neuropathy
(NAION)
3
,
19
Retinal vascular
occlusion
3
Ear and labyrinth disorders
Cardiac disorders
1
Sudden hearing
loss
2
Tachycardia,
Palpitations
Myocardial
infarction,
Unstable angina
pectoris
3
,
Ventricular
arrhythmia
3
Vascular disorders
Flushing
Hypotension
(more commonly
reported when
tadalafil is given
to patients who
are already
taking
antihypertensive
agents),
Hypertension
Respiratory, thoracic and mediastinal disorders
Nasal congestion
Epistaxis
Gastrointestinal disorders
Dyspepsia
Abdominal pain,
Gastro-
oesophageal
reflux
Skin and subcutaneous tissue disorders
Rash,
Hyperhydrosis
(sweating)
Urticaria,
Stevens-Johnson
syndrome
3
,
Exfoliative
dermatitis
3
Musculoskeletal, connective tissue and bone disorders
Back pain,
Myalgia
Reproductive system and breast disorders
Prolonged
erections,
Priapism
3
General disorders and administration site conditions
Chest pain
1
Facial oedema
3
,
Sudden cardiac
death
1,3
(1)Most of the patients in whom these events have been reported had pre-existing cardiovascular risk
factors (see section 4.4).
(2) 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.
(3) Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical
trials
c.
Description of selected adverse reactions
20
A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in
patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities
were not associated with adverse reactions.
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. 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 selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific
phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide,
inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This
results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an
erection. Tadalafil has no effect in the absence of sexual stimulation.
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.
Clinical efficacy and safety
Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of
responsiveness to CIALIS on demand. Tadalafil demonstrated statistically significant improvement in
erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing,
as well as patients’ ability to attain and maintain erections for successful intercourse compared to
placebo as early as 16 minutes following dosing.
Tadalafil 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 CIALIS
10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. In
21
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.
Tadalafil at doses of 2.5, 5, and 10 mg taken once a day was initially evaluated in 3 clinical studies
involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile dysfunction of
various severities (mild, moderate, severe) and etiologies. In the two primary efficacy studies of
general populations, the mean per-subject proportion of successful intercourse attempts were 57 and
67% on CIALIS 5mg, 50% on CIALIS 2.5mg as compared to 31 and 37% with placebo. In the study
in patients with erectile dysfunction secondary to diabetes, the mean per-subject proportion of
successful attempts were 41 and 46% on CIALIS 5mg and 2.5mg, respectively, as compared to 28%
with placebo. Most patients in these three studies were responders to previous on-demand treatment
with PDE5 inhibitors. In a subsequent study, 217 patients who were treatment-naive to PDE5
inhibitors were randomized to CIALIS 5mg once a day vs. placebo. The mean per-subject proportion
of successful sexual intercourse attempts was 68% for CIALIS patients compared to 52% for patients
on placebo.
In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction
secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean
per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-
dose, on demand) of 48% as compared to 17% with placebo.
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 2 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 CIALIS may be taken
with or without food. The time of dosing (morning versus evening) had no clinically relevant effects
on the rate and extent of absorption.
Distribution
The mean volume of distribution is approximately 63 l, 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 2.5 l/h and the mean half-life is 17.5 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).
Linearity/non-linearity
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose
range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma
concentrations are attained within 5 days of once-daily dosing.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction are
similar to pharmacokinetics in subjects without erectile dysfunction.
22
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. 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 (5mg -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.
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. There is
limited clinical data on the safety of CIALIS in patients with severe hepatic insufficiency (Child-Pugh
Class C). There are no available data about the administration of once-a-day dosing of tadalafil to
patients with hepatic impairment. If CIALIS is prescribed once-a-day, a careful individual benefit/risk
evaluation should be undertaken by the prescribing physician.
Patients with diabetes
Tadalafil exposure (AUC) in patients with diabetes was approximately 19 % lower than the AUC
value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
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.
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),
23
iron oxide yellow (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 25°C.
6.5 Nature and contents of container
Aluminium/PVC/PE/PCTFE blisters in cartons of 14 or 28 film-coated tablets.
Not all packs sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Eli Lilly Nederland B.V.
Grootslag 1-5, NL-3991 RA, Houten
The Netherlands
8.
EU/1/02/237/007-008
9.
Date of first authorisation: 12 November 2002
Date of last renewal: 12 November 2007
24
1.
CIALIS 10 mg film-coated tablets
2.
Each tablet contains 10 mg tadalafil.
Excipients: Each coated tablet contains 179 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Light yellow and almond shaped tablets, marked "C 10" on one side.
4.
Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective, sexual stimulation is required.
CIALIS is not indicated for use by women.
Method of administration
CIALIS is available as 2.5, 5, 10 and 20 mg film-coated tablets for oral use.
Posology
Use in adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or
without food.
In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried.
It may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and it is not
recommended for continuous daily use.
In patients who anticipate a frequent use of CIALIS (i.e., at least twice weekly) a once daily regimen
with the lowest doses of CIALIS might be considered suitable, based on patient choice and the
physician’s judgement.
In these patients the recommended dose is 5 mg taken once a day at approximately the same time of
day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.
25
Use in elderly men
Dose adjustments are not required in elderly patients.
Use in men with impaired renal function
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients
with severe renal impairment 10 mg is the maximum recommended dose. Once-a-day dosing of
tadalafil is not recommended in patients with severe renal impairment. (See sectiones 4.4 and 5.2)
Use in men with impaired hepatic function
The recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and with or
without food. There is limited clinical data on the safety of CIALIS in patients with severe hepatic
impairment (Child-Pugh Class C); if 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. Once-a-day dosing has not been
evaluated in patients with hepatic impairment; therefore if prescribed, a careful individual benefit/risk
evaluation should be undertaken by the prescribing physician. (See section 5.2 ).
Use in men with diabetes
Dose adjustments are not required in diabetic patients.
Paediatric population
CIALIS should not be used in individuals below 18 years of age.
Hypersensitivity to the active substance or to any of the excipients.
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 CIALIS to patients who are using any form of organic nitrate is
contraindicated. (See section 4.5).
Agents for the treatment of erectile dysfunction, including CIALIS, must not be used in men with
cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential
cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.
The following groups of patients with cardiovascular disease were not included in clinical trials and
the use of tadalafil is therefore contraindicated:
-
patients with unstable angina or angina occurring during sexual intercourse,
-
patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,
-
patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), or uncontrolled
hypertension,
-
patients with a stroke within the last 6 months.
CIALIS 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).
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and
determine potential underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular
status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil
26
-
patients with myocardial infarction within the last 90 days,
has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1)
and as such potentiate the hypotensive effect of nitrates (see section 4.3).
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina
pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and
tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in
whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not
possible to definitively determine whether these events are related directly to these risk factors, to
CIALIS, to sexual activity, or to a combination of these or other factors.
Visual defects and cases of NAION have been reported in connection with the intake of CIALIS and
other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should
stop taking CIALIS and consult a physician immediately (see section 4.3).
There is limited clinical data on the safety of single-dose administration of CIALIS in patients with
severe hepatic insufficiency (Child-Pugh Class C). If CIALIS is prescribed, a careful individual
benefit/risk evaluation should be undertaken by the prescribing physician.
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.
Agents for the treatment of erectile dysfunction, including CIALIS, 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).
The evaluation of erectile dysfunction should include a determination of potential underlying causes
and the identification of appropriate treatment following an appropriate medical assessment. It is not
known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-nerve-
sparing prostatectomy.
In patients who are taking alpha
1
blockers concomitant administration of CIALIS may lead to
symptomatic hypotension in some patients (see section 4.5). The combination of tadalafil and
doxazosin is not recommended.
Caution should be exercised when prescribing CIALIS to patients using potent CYP3A4 inhibitors
(ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin) as increased tadalafil exposure
(AUC) has been observed if the medicines are combined (see section 4.5).
The safety and efficacy of combinations of CIALIS and other PDE5 inhibitors or other treatments for
erectile dysfunction have not been studied. The patients should be informed not to take CIALIS with
such combinations.
CIALIS 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.
Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard
to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant
interactions at higher doses cannot be completely ruled out.
27
Effects of other substances on tadalafil
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole
(200 mg daily), increased tadalafil (10 mg) 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)
exposure (AUC) 4-fold and C
max
by 22%. Ritonavir, a protease inhibitor (200 mg twice daily), which
is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg)
exposure (AUC) 2-fold with no change in C
max
. Although specific interactions have not been studied,
other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin,
clarithromycin, itraconazole and grapefruit juice should be co-administered with caution as they would
be expected to increase plasma concentrations of tadalafil (see section 4.4)
Consequently the incidence of the undesirable effects listed in section 4.8 might be increased.
The role of transporters (for example p-glycoprotein) in the disposition of tadalafil is not known.
There is thus the potential of drug interactions mediated by inhibition of transporters.
A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values for
tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil;
the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4 such as phenobarbital,
phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of tadalafil on other medicinal products
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of
nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is
contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects
receiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various
times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had
elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of CIALIS (2,5 mg – 20
mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least
48 hours should have elapsed after the last dose of CIALIS before nitrate administration is considered.
In such circumstances, nitrates should only be administered under close medical supervision with
appropriate haemodynamic monitoring.
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. However, caution should be exercised when using tadalafil in
patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at
minimal dosage and progressively adjusted.
In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of
antihypertensive agents was examined. Major classes of antihypertensive agents were studied,
including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors
(enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and
angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides,
calcium channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10 mg except for studies
with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no
clinically significant interaction with any of these classes. In another clinical pharmacology study
tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In subjects
taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the
degree of blood-pressure control. In this regard, study subjects whose blood pressure was well
controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects
whose blood pressure was not controlled, the reduction was greater although this reduction was not
associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant
28
antihypertensive medicines, tadalafil 20 mg may induce a blood pressure decrease, which (with the
exception of alpha blockers -see above-) is, in general, minor and not likely to be clinically relevant.
Analysis of phase 3 clinical trial data showed no difference in adverse events in patients taking
tadalafil with or without antihypertensive medicines. However, appropriate clinical advice should be
given to patients regarding a possible decrease in blood pressure when they are treated with
antihypertensive medicines.
When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase
inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only
pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor
and was of no clinical significance in this study, it should be considered when co-administering these
medicines.
Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a
similar increase may be expected with oral administration of terbutaline, although the clinical
consequence of this is uncertain.
Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co-
administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations
were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to
maximize the rate of alcohol absorption (overnight fast with no food until 2 hours after 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. When tadalafil was administered with lower
doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar
frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil
(10 mg).
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of
medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not
inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and
CYP2C19.
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.
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic
acid.
Specific interaction studies with antidiabetic agents were not conducted.
CIALIS is not indicated for use by women.
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 CIALIS during pregnancy.
Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A
risk to the suckling child cannot be excluded. CIALIS should not be used during breast feeding.
29
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 CIALIS, before driving or operating machinery.
a.
Summary of the safety profile
The most commonly reported adverse reactions were headache and dyspepsia. 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
The table below lists the adverse reactions reported in erectile dysfunction placebo-controlled clinical
trials in patients treated with CIALIS on demand and daily dosing with doses within the currently
approved dosing range for CIALIS. Adverse reactions are also included that have been reported from
postmarketing surveillance in patients taking CIALIS.
Adverse reactions
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 (events not reported in registration trials cannot be estimated from postmarketing
spontaneous reports)
Very common
(≥1/10)
Common
(≥1/100 to <1/10)
Uncommon
(
≥
1/1000 to
<
1/100)
Rare
(
≥
1/10,000 to
<
1/1000)
Immune system disorders
Hypersensitivity
reactions
Nervous System disorders
Headache
Dizziness
Stroke
1
(including
haemorrhagic
events), Syncope,
Transient
ischaemic
attacks
1
,
Migraine
3
,
Seizures,
Transient
amnesia
Eye disorders
Blurred vision,
Sensations
described as eye
pain,
Visual field
defect, Swelling
of eyelids,
Conjunctival
hyperaemia,
Non-arteritic
anterior ischemic
optic neuropathy
(NAION)
3
,
Retinal vascular
occlusion
3
Ear and labyrinth disorders
Sudden hearing
30
Cardiac disorders
1
loss
2
Tachycardia,
Palpitations
Myocardial
infarction,
Unstable angina
pectoris
3
,
Ventricular
arrhythmia
3
Vascular disorders
Flushing
Hypotension
(more commonly
reported when
tadalafil is given
to patients who
are already
taking
antihypertensive
agents),
Hypertension
Respiratory, thoracic and mediastinal disorders
Nasal congestion
Epistaxis
Gastrointestinal disorders
Dyspepsia
Abdominal pain,
Gastro-
oesophageal
reflux
Skin and subcutaneous tissue disorders
Rash,
Hyperhydrosis
(sweating)
Urticaria,
Stevens-Johnson
syndrome
3
,
Exfoliative
dermatitis
3
Musculoskeletal, connective tissue and bone disorders
Back pain,
Myalgia
Reproductive system and breast disorders
Prolonged
erections,
Priapism
3
General disorders and administration site conditions
Chest pain
1
Facial oedema
3
,
Sudden cardiac
death
1,3
(1) Most of the patients in whom these events have been reported had pre-existing cardiovascular risk
factors (See section 4.4).
(2) 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.
(3) Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical
trials
c.
Description of selected adverse reactions
A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in
patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities
were not associated with adverse reactions.
31
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. 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 selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific
phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide,
inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This
results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an
erection. Tadalafil has no effect in the absence of sexual stimulation.
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.
Clinical efficacy and safety
Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of
responsiveness to CIALIS. Tadalafil demonstrated statistically significant improvement in erectile
function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well
as patients’ ability to attain and maintain erections for successful intercourse compared to placebo as
early as 16 minutes following dosing.
Tadalafil 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 CIALIS
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.
Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients,
including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies,
32
ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year
in duration. In the primary efficacy studies of general populations, 81% of patients reported that
CIALIS improved their erections as compared to 35% with placebo. Also, patients with erectile
dysfunction in all severity categories reported improved erections whilst taking CIALIS (86%, 83%,
and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with
placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in CIALIS
treated patients as compared to 32% with placebo.
In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction
secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean
per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-
dose, on demand) of 48% as compared to 17% with placebo.
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 2 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 CIALIS may be taken
with or without food. The time of dosing (morning versus evening) had no clinically relevant effects
on the rate and extent of absorption.
Distribution
The mean volume of distribution is approximately 63 l, 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 2.5 l/h and the mean half-life is 17.5 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).
Linearity/non-linearity
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose
range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma
concentrations are attained within 5 days of once-daily dosing.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction are
similar to pharmacokinetics in subjects without erectile dysfunction.
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. This effect of age is not
clinically significant and does not warrant a dose adjustment.
Renal insufficiency
33
In clinical pharmacology studies using single-dose tadalafil (5mg - 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.
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. There is
limited clinical data on the safety of CIALIS in patients with severe hepatic insufficiency (Child-Pugh
Class C). If CIALIS 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 diabetes
Tadalafil exposure (AUC) in patients with diabetes was approximately 19 % lower than the AUC
value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
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.
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),
talc.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
34
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 4 film-coated tablets.
6.6 Special precautions for disposal
No special requirements.
7.
Eli Lilly Nederland B.V.
Grootslag 1-5, NL-3991 RA, Houten
The Netherlands
8.
EU/1/02/237/001
9.
Date of first authorisation: 12 November 2002
Date of last renewal: 12 November 2007
35
1.
CIALIS 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).
Yellow and almond shaped tablets, marked "C 20" on one side.
4.
Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective, sexual stimulation is required.
CIALIS is not indicated for use by women.
Method of administration
CIALIS is available as 2.5, 5, 10 and 20 mg film-coated tablets for oral use.
Posology
Use in adult men
In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or
without food. In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg
might be tried.
It may be taken at least 30 minutes prior to sexual activity.
The maximum dose frequency is once per day.
Tadalafil 10 mg and 20 mg is intended for use prior to anticipated sexual activity and it is not
recommended for continuous daily use.
In patients who anticipate a frequent use of CIALIS (i.e., at least twice weekly) a once daily regimen
with the lowest doses of CIALIS might be considered suitable, based on patient choice and the
physician’s judgement.
In these patients the recommended dose is 5 mg taken once a day at approximately the same time of
day. The dose may be decreased to 2.5 mg once a day based on individual tolerability.
The appropriateness of continued use of the daily regimen should be reassessed periodically.
36
Use in elderly men
Dose adjustments are not required in elderly patients.
Use in men with impaired renal function
Dose adjustments are not required in patients with mild to moderate renal impairment. For patients
with severe renal impairment 10 mg is the maximum recommended dose. Once-a-day dosing of
tadalafil is not recommended in patients with severe renal impairment. (See sectiones 4.4 and 5.2)
Use in men with impaired hepatic function
The recommended dose of CIALIS is 10 mg taken prior to anticipated sexual activity and with or
without food. There is limited clinical data on the safety of CIALIS in patients with severe hepatic
impairment (Child-Pugh Class C); if 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. Once-a-day dosing has not been
evaluated in patients with hepatic impairment; therefore if prescribed, a careful individual benefit/risk
evaluation should be undertaken by the prescribing physician. (See section 5.2).
Use in men with diabetes
Dose adjustments are not required in diabetic patients.
Paediatric population
CIALIS should not be used in individuals below 18 years of age.
Hypersensitivity to the active substance or to any of the excipients.
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 CIALIS to patients who are using any form of organic nitrate is
contraindicated. (See section 4.5).
Agents for the treatment of erectile dysfunction, including CIALIS, must not be used in men with
cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential
cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.
The following groups of patients with cardiovascular disease were not included in clinical trials and
the use of tadalafil is therefore contraindicated:
-
patients with myocardial infarction within the last 90 days,
-
patients with unstable angina or angina occurring during sexual intercourse,
-
patients with New York Heart Association Class 2 or greater heart failure in the last 6 months,
-
patients with uncontrolled arrhythmias, hypotension (< 90/50 mm Hg), or uncontrolled
hypertension,
-
patients with a stroke within the last 6 months.
CIALIS 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).
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and
determine potential underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular
status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil
37
has vasodilator properties, resulting in mild and transient decreases in blood pressure (see section 5.1)
and as such potentiate the hypotensive effect of nitrates (see section 4.3).
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina
pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and
tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in
whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not
possible to definitively determine whether these events are related directly to these risk factors, to
CIALIS, to sexual activity, or to a combination of these or other factors.
Visual defects and cases of NAION have been reported in connection with the intake of CIALIS and
other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should
stop taking CIALIS and consult a physician immediately (see section 4.3).
There is limited clinical data on the safety of single-dose administration of CIALIS in patients with
severe hepatic insufficiency (Child-Pugh Class C). If CIALIS is prescribed, a careful individual
benefit/risk evaluation should be undertaken by the prescribing physician.
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.
Agents for the treatment of erectile dysfunction, including CIALIS, 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).
The evaluation of erectile dysfunction should include a determination of potential underlying causes
and the identification of appropriate treatment following an appropriate medical assessment. It is not
known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-nerve-
sparing prostatectomy.
In patients who are taking alpha
1
blockers concomitant administration of CIALIS may lead to
symptomatic hypotension in some patients (see section 4.5). The combination of tadalafil and
doxazosin is not recommended.
Caution should be exercised when prescribing CIALIS to patients using potent CYP3A4 inhibitors
(ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin) as increased tadalafil exposure
(AUC) has been observed if the medicines are combined (see section 4.5).
The safety and efficacy of combinations of CIALIS and other PDE5 inhibitors or other treatments for
erectile dysfunction have not been studied. The patients should be informed not to take CIALIS with
such combinations.
CIALIS 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.
Interaction studies were conducted with 10 mg and/or 20 mg tadalafil, as indicated below. With regard
to those interaction studies where only the 10 mg tadalafil dose was used, clinically relevant
interactions at higher doses cannot be completely ruled out.
38
Effects of other substances on tadalafil
Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole
(200 mg daily), increased tadalafil (10 mg) 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)
exposure (AUC) 4-fold and C
max
by 22%. Ritonavir, a protease inhibitor (200 mg twice daily), which
is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg)
exposure (AUC) 2-fold with no change in C
max
. Although specific interactions have not been studied,
other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin,
clarithromycin, itraconazole and grapefruit juice should be co-administered with caution as they would
be expected to increase plasma concentrations of tadalafil (see section 4.4). Consequently the
incidence of the undesirable effects listed in section 4.8 might be increased.
The role of transporters (for example p-glycoprotein) in the disposition of tadalafil is not known.
There is thus the potential of drug interactions mediated by inhibition of transporters.
A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88 %, relative to the AUC values for
tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil;
the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4 such as phenobarbital,
phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of tadalafil on other medicinal products
In clinical studies, tadalafil (5, 10 and 20 mg) was shown to augment the hypotensive effects of
nitrates. Therefore, administration of CIALIS to patients who are using any form of organic nitrate is
contraindicated (see section 4.3). Based on the results of a clinical study in which 150 subjects
receiving daily doses of tadalafil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various
times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had
elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of CIALIS (2.5 mg – 20
mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least
48 hours should have elapsed after the last dose of CIALIS before nitrate administration is considered.
In such circumstances, nitrates should only be administered under close medical supervision with
appropriate haemodynamic monitoring.
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. However, caution should be exercised when using tadalafil in
patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at
minimal dosage and progressively adjusted.
In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of
antihypertensive agents was examined. Major classes of antihypertensive agents were studied,
including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors
(enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and
angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides,
calcium channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10 mg except for studies
with angiotensin II receptor blockers and amlodipine in which a 20 mg dose was applied) had no
clinically significant interaction with any of these classes. In another clinical pharmacology study
tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In subjects
taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the
degree of blood-pressure control. In this regard, study subjects whose blood pressure was well
controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects
whose blood pressure was not controlled, the reduction was greater although this reduction was not
associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant
39
antihypertensive medicines, tadalafil 20 mg may induce a blood pressure decrease, which (with the
exception of alpha blockers -see above-) is, in general, minor and not likely to be clinically relevant.
Analysis of phase 3 clinical trial data showed no difference in adverse events in patients taking
tadalafil with or without antihypertensive medicines. However, appropriate clinical advice should be
given to patients regarding a possible decrease in blood pressure when they are treated with
antihypertensive medicines.
When tadalafil 10 mg was administered with theophylline (a non-selective phosphodiesterase
inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only
pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor
and was of no clinical significance in this study, it should be considered when co-administering these
medicines.
Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a
similar increase may be expected with oral administration of terbutaline, although the clinical
consequence of this is uncertain.
Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co-
administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations
were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to
maximize the rate of alcohol absorption (overnight fast with no food until 2 hours after 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. When tadalafil was administered with lower
doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar
frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil
(10 mg).
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of
medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not
inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and
CYP2C19.
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.
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic
acid.
Specific interaction studies with antidiabetic agents were not conducted.
CIALIS is not indicated for use by women.
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 CIALIS during pregnancy.
Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A
risk to the suckling child cannot be excluded. CIALIS should not be used during breast feeding.
40
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 CIALIS, before driving or operating machinery.
a.
Summary of the safety profile
The most commonly reported adverse reactions are headache and dyspepsia. 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
The table below lists the adverse reactions reported in erectile dysfunction placebo-controlled clinical
trials in patients treated with CIALIS on demand and daily dosing with doses within the currently
approved dosing range for CIALIS. Adverse reactions are also included that have been reported from
postmarketing surveillance in patients taking CIALIS.
Adverse reactions
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 (events not reported in registration trials cannot be estimated from postmarketing
spontaneous reports)
Very common
(≥1/10)
Common
(≥1/100 to <1/10)
Uncommon
(
≥
1/1000 to
<
1/100)
Rare
(
≥
1/10,000 to
<
1/1000)
Immune system disorders
Hypersensitivity
reactions
Nervous System disorders
Headache
Dizziness
Stroke
1
(including
haemorrhagic
events), Syncope,
Transient
ischaemic
attacks
1
,
Migraine
3
,
Seizures,
Transient
amnesia
Eye disorders
Blurred vision,
Sensations
described as eye
pain
Visual field
defect, Swelling
of eyelids,
Conjunctival
hyperaemia,
Non-arteritic
anterior ischemic
optic neuropathy
(NAION)
3
,
Retinal vascular
occlusion
3
Ear and labyrinth disorders
Sudden hearing
loss
2
41
Cardiac disorders
1
Tachycardia,
Palpitations
Myocardial
infarction,
Unstable angina
pectoris
3
,
Ventricular
arrhythmia
3
Vascular disorders
Flushing
Hypotension
(more commonly
reported when
tadalafil is given
to patients who
are already
taking
antihypertensive
agents),
Hypertension
Respiratory, thoracic and mediastinal disorders
Nasal congestion
Epistaxis
Gastrointestinal disorders
Dyspepsia
Abdominal pain,
Gastro-
oesophageal
reflux
Skin and subcutaneous tissue disorders
Rash,
Hyperhydrosis
(sweating)
Urticaria,
Stevens-Johnson
syndrome
3
,
Exfoliative
dermatitis
3
Musculoskeletal, connective tissue and bone disorders
Back pain,
Myalgia
Reproductive system and breast disorders
Prolonged
erections,
Priapism
3
General disorders and administration site conditions
Chest pain
1
Facial oedema
3
,
Sudden cardiac
death
1,3
(1) Most of the patients in whom these events have been reported had pre-existing cardiovascular risk
factors (See section 4.4).
(2) 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.
(3) Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical
trials
c.
Description of selected adverse reactions
A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in
patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities
were not associated with adverse reactions.
42
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. 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 selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific
phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide,
inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This
results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an
erection. Tadalafil has no effect in the absence of sexual stimulation.
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.
Clinical efficacy and safety
Three clinical studies were conducted in 1054 patients in an at-home setting to define the period of
responsiveness to CIALIS. Tadalafil demonstrated statistically significant improvement in erectile
function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well
as patients’ ability to attain and maintain erections for successful intercourse compared to placebo as
early as 16 minutes following dosing.
Tadalafil 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 CIALIS
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.
Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients,
including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies,
ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year
43
in duration. In the primary efficacy studies of general populations, 81% of patients reported that
CIALIS improved their erections as compared to 35% with placebo. Also, patients with erectile
dysfunction in all severity categories reported improved erections whilst taking CIALIS (86%, 83%,
and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with
placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in CIALIS
treated patients as compared to 32% with placebo.
In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction
secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean
per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-
dose, on demand) of 48% as compared to 17% with placebo.
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 2 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 CIALIS may be taken
with or without food. The time of dosing (morning versus evening) had no clinically relevant effects
on the rate and extent of absorption.
Distribution
The mean volume of distribution is approximately 63 l, 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 2.5 l/h and the mean half-life is 17.5 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).
Linearity/non-linearity
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose
range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma
concentrations are attained within 5 days of once-daily dosing.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction are
similar to pharmacokinetics in subjects without erectile dysfunction.
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. 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
44
(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.
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. There is
limited clinical data on the safety of CIALIS in patients with severe hepatic insufficiency (Child-Pugh
Class C). If CIALIS 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 diabetes
Tadalafil exposure (AUC) in patients with diabetes was approximately 19 % lower than the AUC
value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
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.
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),
talc.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
45
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 2, 4, 8, 10 and 12 film-coated tablets.
Not all packs sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Eli Lilly Nederland B.V.
Grootslag 1-5, NL-3991 RA, Houten
The Netherlands
8.
EU/1/02/237/002-005, 009
9.
Date of first authorisation: 12 November 2002
Date of last renewal: 12 November 2007
46
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
47
A
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B
CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription
•
CONDITIONS OR RESTRICTIONS WITH REGARDS TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The Marketing Authorisation Holder must ensure that the system of pharmacovigilance, presented in
Module 1.8.1. of the Marketing Authorisation, is in place and functioning before and whilst the
product is on the market
Risk Management Plan
The Marketing Authorisation Holder commits to performing the studies additional pharmacovigilance
activities detailed in the Pharmacovigilance Plan, as agreed in version 1 of the Risk Management Plan
(RPM) presented in Module 1.8.2. of the Marketing Authorisation and 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 minimization activities.
•
within 60 days of an important (pharmacovigilance or risk minimization) milestone being
reached.
•
at the request of the EMEA.
PSUR
The Marketing Authorisation Holder will continue to submit yearly PSURs unless otherwise specified
by the CHMP.
48
ANNEX III
LABELLING AND PACKAGE LEAFLET
49
A. LABELLING
50
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON TEXT
1.
CIALIS 2.5 mg film-coated tablets
tadalafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 2.5 mg tadalafil
3.
LIST OF EXCIPIENTS
lactose monohydrate
See leaflet for further information.
4.
28 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral once-a-day use. Read the package leaflet before use.
How to take CIALIS Once-A-Day
1. Start with the pill from the blister pack that corresponds with the day you start taking CIALIS.
2. Take CIALIS with water every day at approximately the same time, either with
or without food.
3
.
When taken once a day CIALIS allows you to obtain an erection, when sexually stimulated, at any
time point during the 24 hours of the day. You and your partner will need to engage in foreplay, just as
you would if you were not taking a medicine for erectile dysfunction.
•
Always take CIALIS exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
•
Drinking alcohol may affect your ability to get an erection so avoid excessive drinking with
CIALIS.
•
You should NOT take CIALIS more than once a day. If you take more than you should, tell
your doctor.
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
51
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
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/1/02/237/006
13. BATCH NUMBER
Lot.
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
cialis 2.5 mg
52
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON TEXT
1.
CIALIS 5 mg film-coated tablets
tadalafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 5 mg tadalafil
3.
LIST OF EXCIPIENTS
lactose monohydrate
See leaflet for further information.
4.
14 film-coated tablets
28 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral once-a-day use. Read the package leaflet before use.
How to take CIALIS Once-A-Day
1. Start with the pill from the blister pack that corresponds with the day you start taking CIALIS.
2. Take CIALIS with water every day at approximately the same time, either with or without food.
3
.
When taken once a day CIALIS allows you to obtain an erection, when sexually stimulated, at any
time point during the 24 hours of the day. You and your partner will need to engage in foreplay, just as
you would if you were not taking a medicine for erectile dysfunction.
•
Always take CIALIS exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
•
Drinking alcohol may affect your ability to get an erection so avoid excessive drinking with
CIALIS.
•
You should NOT take CIALIS more than once a day. If you take more than you should, tell
your doctor.
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.
53
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 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
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/1/02/237/007-008
13. BATCH NUMBER
Lot.
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
cialis 5 mg
54
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON TEXT
1.
CIALIS 10 mg film-coated tablets
tadalafil
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 10 mg tadalafil
3.
LIST OF EXCIPIENTS
lactose monohydrate
See leaflet for further information.
4.
4 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
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
55
Eli Lilly Nederland B.V.
Grootslag 1-5, NL-3991 RA, Houten
The Netherlands
EU/1/02/237/001
13. BATCH NUMBER
Lot.
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
cialis 10 mg
56
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON TEXT
1.
CIALIS 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.
2 film-coated tablets
4 film-coated tablets
8 film-coated tablets
10 film-coated tablets
12 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.
57
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
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/1/02/237/002-005, 009
13. BATCH NUMBER
Lot.
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
cialis 20 mg
58
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
CIALIS 2.5 mg tablets
tadalafil
2.
Lilly
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot.
5.
OTHER
MON, TUE, WED, THU, FRI, SAT, SUN
59
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
CIALIS 5 mg tablets
tadalafil
2.
Lilly
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot.
5.
OTHER
MON, TUE, WED, THU, FRI, SAT, SUN
60
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
CIALIS 10 mg tablets
tadalafil
2.
Lilly
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot.
5.
OTHER
61
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
CIALIS 20 mg tablets
tadalafil
2.
Lilly
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot.
5.
OTHER
62
B. PACKAGE LEAFLET
63
PACKAGE LEAFLET: INFORMATION FOR THE USER
CIALIS 2.5 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 CIALIS is and what it is used for
2.
Before you take CIALIS
4.
Possible side effects
5
How to store CIALIS
6.
Further information
1.
WHAT CIALIS IS AND WHAT IT IS USED FOR
CIALIS is a treatment for men with erectile dysfunction. This is when a man cannot get, or keep a
hard, erect penis suitable for sexual activity.
CIALIS belongs to a group of medicines called phosphodiesterase type 5 inhibitors. Following sexual
stimulation CIALIS works by helping the blood vessels in your penis to relax, allowing the flow of
blood into your penis. The result of this is improved erectile function. CIALIS will not help you if you
do not have erectile dysfunction.
It is important to note that CIALIS does not work if there is no sexual stimulation. You and your
partner will need to engage in foreplay, just as you would if you were not taking a medicine for
erectile dysfunction.
2.
BEFORE YOU TAKE CIALIS
Do not take CIALIS
-
if you are allergic (hypersensitive) to tadalafil or any of the other ingredients of CIALIS.
-
if you are taking any form of organic nitrate or nitric oxide donors such as amyl nitrite. This is a
group of medicines (“nitrates”) used in the treatment of angina pectoris (“chest pain”). CIALIS
has been shown to increase the effects of these medicines. If you are taking any form of nitrate
or are unsure tell your doctor.
-
if you have serious heart disease or have had a recent heart attack.
-
if you have had a recent stroke.
-
if you have low blood pressure or uncontrolled high blood pressure.
- if you have ever had loss of vision because of non-arteritic anterior ischemic optic neuropathy
(NAION), a condition sometimes described as “stroke of the eye”.
64
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to take CIALIS
Take special care with CIALIS
Be aware that sexual activity carries a possible risk to patients with heart disease because it puts an
extra strain on your heart. If you have a heart problem you should tell your doctor.
The following are reasons why CIALIS may also not be suitable for you. If any of them apply to you,
talk to your doctor before you take the medicine:
-
You have sickle cell anaemia (an abnormality of red blood cells), multiple myeloma (cancer of
the bone marrow), leukaemia (cancer of the blood cells) or any deformation of your penis.
-
You have a serious liver problem.
-
You have a severe kidney problem.
It is not known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-
nerve-sparing prostatectomy.
If you experience sudden decrease or loss of vision, stop taking CIALIS and contact your doctor
immediately.
CIALIS is not intended for use by women or by adolescents under the age of 18.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription, because they might interact.
This is particulary important if you are treated with nitrates as you should not take CIALIS if you are
taking these medicines.
A type of medicine called an alpha blocker is sometimes used to treat high blood pressure and
enlarged prostate. Tell your doctor if you are being treated for either of these conditions or if you take
other medicines to treat high blood pressure.
If you are taking medicines that can inhibit an enzyme called CYP3A4 (for example ketoconazole or
protease inhibitors for treatment of HIV) the frequency of side effects might increase.
Do not take CIALIS with other medicines if your doctor tells you that you may not.
You should not use CIALIS together with any other treatments for erectile dysfunction.
Taking CIALIS with food and drink
You may take CIALIS with or without food.
Information on the effect of alcohol is in section 3.
Driving and using machines
Some men taking CIALIS in clinical studies have reported dizziness. Check carefully how you react to
the medicines before driving or using any machinery.
Important information about some of the ingredients of CIALIS:
CIALIS contains lactose. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicinal product.
65
3.
HOW TO TAKE CIALIS
Always take CIALIS exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Once a day dosing of CIALIS may be useful to men who anticipate having sexual activity two or more
times per week. The recommended dose is one 5 mg tablet taken once a day at approximately the same
time of the day. Your doctor may adjust the dose to 2.5 mg based on your response to CIALIS.
CIALIS tablets are for oral use. Swallow the tablet whole with some water. You may take CIALIS
with or without food.
When taken once a day CIALIS allows you to obtain an erection, when sexually stimulated, at any
time point during the 24 hours of the day. It is important to note that CIALIS does not work if there is
no sexual stimulation. You and your partner will need to engage in foreplay, just as you would if you
were not taking a medicine for erectile dysfunction.
Drinking alcohol may affect your ability to get an erection. Drinking alcohol may temporarily lower
your blood pressure. If you have taken or are planning to take CIALIS, avoid excessive drinking
(blood alcohol level of 0.08% or greater), since this may increase the risk of dizziness when standing
up.
You should NOT take CIALIS more than once a day.
If you take more CIALIS than you should
Tell your doctor.
If you forget to take CIALIS
Do not take a double dose to make up for a forgotten tablet.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, CIALIS can cause side effects, although not everybody gets them. These effects are
normally mild to moderate in nature.
In this leaflet, when a side effect is described as “very common” this means that it has been reported in
at least 1 in 10 patients taking the medicine. When a side effect is described as “common” this means
that it has been reported in more than 1 in every 100 patients but less than 1 in every 10 patients. When
a side effect is described as “uncommon”, this means it has been reported in more than 1 in every 1,000
patients, but less than 1 in every 100 patients. When a side effect is described as “rare”, this means it
has been reported in more than 1 in every 10,000 patients, but less than 1 in every 1,000 patients.
Very commonly reported side effects in patients taking CIALIS were headache.
Commonly reported side effects in patients taking CIALIS include back pain, muscle aches, facial
flushing, nasal congestion, dizziness, and indigestion.
Uncommon side effects are allergic reactions including rashes, abdominal pain, reflux, blurred vision,
eye pain, increased sweating, pounding heartbeat sensation, a fast heart rate, high blood pressure, low
blood pressure and chest pain. In case of chest pain occurring during or after sexual activity you
should NOT use nitrates but you should seek immediate medical assistance.
Rare side effects in patients taking CIALIS include fainting, seizures and passing memory loss,
swelling of the eyelids, red eyes, sudden decrease or loss of hearing, hives and nose bleeds.
66
In rare instances it is possible that a prolonged and possibly painful erection may occur after taking
CIALIS. If you have such an erection, which lasts continuously for more than 4 hours, you should
contact a doctor immediately.
Heart attack and stroke have also been reported rarely in men taking CIALIS. Most, but not all of
these men had known heart problems before taking this medicine. It is not possible to determine
whether these events were directly related to CIALIS.
Partial, sudden, temporary, or permanent decrease or loss of vision in one or both eyes has been rarely
reported.
Some additional side effects have been reported in men taking CIALIS at an estimated frequency of
rare that were not seen in clinical trials. These include migraine, swelling of the face, serious skin
rashes some disorders affecting blood flow to the eyes, irregular heartbeats, angina and sudden cardiac
death.
Effects were seen in one animal species that might indicate impairment of fertility. Subsequent studies
in man suggest that this effect is unlikely in humans, although 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.
5.
HOW TO STORE CIALIS
Keep out of the reach and sight of children.
Do not use CIALIS 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 CIALIS contains
The active substance is tadalafil. Each tablet contains 2.5 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 CIALIS looks like and contents of the pack
CIALIS 2.5 mg strength comes as orange-yellow film-coated tablets. They are in the shape of almonds
and have "C 2 ½" marked on one side.
CIALIS 2.5 mg is available in blister packs containing 28 tablets.
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.
67
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
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε
Τηλ: +30 210 629 4600
Polska
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
68
PACKAGE LEAFLET: INFORMATION FOR THE USER
CIALIS 5 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 CIALIS is and what it is used for
2.
Before you take CIALIS
4.
Possible side effects
5
How to store CIALIS
6.
Further information
1.
WHAT CIALIS IS AND WHAT IT IS USED FOR
CIALIS is a treatment for men with erectile dysfunction. This is when a man cannot get, or keep a
hard, erect penis suitable for sexual activity.
CIALIS belongs to a group of medicines called phosphodiesterase type 5 inhibitors. Following sexual
stimulation CIALIS works by helping the blood vessels in your penis to relax, allowing the flow of
blood into your penis. The result of this is improved erectile function. CIALIS will not help you if you
do not have erectile dysfunction.
It is important to note that CIALIS does not work if there is no sexual stimulation. You and your
partner will need to engage in foreplay, just as you would if you were not taking a medicine for
erectile dysfunction.
2.
BEFORE YOU TAKE CIALIS
Do not take CIALIS
-
if you are allergic (hypersensitive) to tadalafil or any of the other ingredients of CIALIS.
-
if you are taking any form of organic nitrate or nitric oxide donors such as amyl nitrite. This is a
group of medicines (“nitrates”) used in the treatment of angina pectoris (“chest pain”). CIALIS
has been shown to increase the effects of these medicines. If you are taking any form of nitrate
or are unsure tell your doctor.
-
if you have serious heart disease or have had a recent heart attack.
-
if you have had a recent stroke.
-
if you have low blood pressure or uncontrolled high blood pressure.
- if you have ever had loss of vision because of non-arteritic anterior ischemic optic neuropathy
(NAION), a condition sometimes described as “stroke of the eye”.
69
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to take CIALIS
Take special care with CIALIS
Be aware that sexual activity carries a possible risk to patients with heart disease because it puts an
extra strain on your heart. If you have a heart problem you should tell your doctor.
The following are reasons why CIALIS may also not be suitable for you. If any of them apply to you,
talk to your doctor before you take the medicine:
-
You have sickle cell anaemia (an abnormality of red blood cells), multiple myeloma (cancer of
the bone marrow), leukaemia (cancer of the blood cells) or any deformation of your penis.
-
You have a serious liver problem.
-
You have a severe kidney problem.
It is not known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-
nerve-sparing prostatectomy
If you experience sudden decrease or loss of vision, stop taking CIALIS and contact your doctor
immediately.
CIALIS is not intended for use by women or by adolescents under the age of 18.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription, because they might interact.
This is particularly important if you are treated with nitrates as you should not take CIALIS if you are
taking these medicines.
A type of medicine called an alpha blocker is sometimes used to treat high blood pressure and
enlarged prostate. Tell your doctor if you are being treated for either of these conditions or if you take
other medicines to treat high blood pressure.
If you are taking medicines that can inhibit an enzyme called CYP3A4 (for example ketoconazole or
protease inhibitors for treatment of HIV) the frequency of side effects might increase.
Do not take CIALIS with other medicines if your doctor tells you that you may not.
You should not use CIALIS together with any other treatments for erectile dysfunction.
Taking CIALIS with food and drink
You may take CIALIS with or without food.
Information on the effect of alcohol is in section 3.
Driving and using machines
Some men taking CIALIS in clinical studies have reported dizziness. Check carefully how you react to
the medicines before driving or using any machinery.
Important information about some of the ingredients of CIALIS:
CIALIS contains lactose. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicinal product.
70
3.
HOW TO TAKE CIALIS
Always take CIALIS exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Once a day dosing of CIALIS may be useful to men who anticipate having sexual activity two or more
times per week. The recommended dose is one 5 mg tablet taken once a day at approximately the same
time of the day. Your doctor may adjust the dose to 2.5 mg based on your response to CIALIS.
CIALIS tablets are for oral use. Swallow the tablet whole with some water. You may take CIALIS
with or without food.
When taken once a day CIALIS allows you to obtain an erection, when sexually stimulated, at any
time point during the 24 hours of the day. It is important to note that CIALIS does not work if there is
no sexual stimulation. You and your partner will need to engage in foreplay, just as you would if you
were not taking a medicine for erectile dysfunction.
Drinking alcohol may affect your ability to get an erection. Drinking alcohol may temporarily lower
your blood pressure. If you have taken or are planning to take CIALIS, avoid excessive drinking
(blood alcohol level of 0.08% or greater), since this may increase the risk of dizziness when standing
up.
You should NOT take CIALIS more than once a day.
If you take more CIALIS than you should
Tell your doctor.
If you forget to take CIALIS
Do not take a double dose to make up for a forgotten tablet.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, CIALIS can cause side effects, although not everybody gets them. These effects are
normally mild to moderate in nature.
In this leaflet, when a side effect is described as “very common” this means that it has been reported in
at least 1 in 10 patients taking the medicine. When a side effect is described as “common” this means
that it has been reported in more than 1 in every 100 patients but less than 1 in every 10 patients. When
a side effect is described as “uncommon”, this means it has been reported in more than 1 in every 1,000
patients, but less than 1 in every 100 patients. When a side effect is described as “rare”, this means it
has been reported in more than 1 in every 10,000 patients, but less than 1 in every 1,000 patients.
Very commonly reported side effects in patients taking CIALIS were headache.
Commonly reported side effects in patients taking CIALIS include back pain, muscle aches, facial
flushing, nasal congestion, dizziness and indigestion.
Uncommon side effects are allergic reactions including rashes, abdominal pain, reflux, blurred vision,
eye pain, increased sweating, pounding heartbeat sensation, a fast heart rate, high blood pressure, low
blood pressure and chest pain. In case of chest pain occurring during or after sexual activity you
should NOT use nitrates but you should seek immediate medical assistance.
Rare side effects in patients taking CIALIS include fainting, migraine, seizures and passing memory
loss, swelling of the eyelids, red eyes, sudden decrease or loss of hearing, hives and nose bleeds.
71
In rare instances it is possible that a prolonged and possibly painful erection may occur after taking
CIALIS. If you have such an erection, which lasts continuously for more than 4 hours, you should
contact a doctor immediately.
Heart attack and stroke have also been reported rarely in men taking CIALIS. Most, but not all of
these men had known heart problems before taking this medicine. It is not possible to determine
whether these events were directly related to CIALIS.
Partial, sudden, temporary, or permanent decrease or loss of vision in one or both eyes has been rarely
reported.
Some additional side effects have been reported in men taking CIALIS at an estimated frequency of
rare that were not seen in clinical trials. These include migraine, swelling of the face, serious skin
rashes, some disorders affecting blood flow to the eyes, irregular heartbeats, angina and sudden
cardiac death.
Effects were seen in one animal species that might indicate impairment of fertility. Subsequent studies
in man suggest that this effect is unlikely in humans, although 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.
5.
HOW TO STORE CIALIS
Keep out of the reach and sight of children.
Do not use CIALIS 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 25°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 CIALIS contains
The active substance is tadalafil. Each tablet contains 5 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), talc.
What CIALIS looks like and contents of the pack
CIALIS 5 mg strength comes as light yellow film-coated tablets. They are in the shape of almonds and
have "C 5" marked on one side.
CIALIS 5 mg is available in blister packs containing 14 or 28 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
72
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
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε
Τηλ: +30 210 629 4600
Polska
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}
73
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu
74
PACKAGE LEAFLET: INFORMATION FOR THE USER
CIALIS 10 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 CIALIS is and what it is used for
2.
Before you take CIALIS
4.
Possible side effects
5
How to store CIALIS
6.
Further information
1.
WHAT CIALIS IS AND WHAT IT IS USED FOR
CIALIS is a treatment for men with erectile dysfunction. This is when a man cannot get, or keep a
hard, erect penis suitable for sexual activity.
CIALIS belongs to a group of medicines called phosphodiesterase type 5 inhibitors. Following sexual
stimulation CIALIS works by helping the blood vessels in your penis to relax, allowing the flow of
blood into your penis. The result of this is improved erectile function. CIALIS will not help you if you
do not have erectile dysfunction.
It is important to note that CIALIS does not work if there is no sexual stimulation. You and your
partner will need to engage in foreplay, just as you would if you were not taking a medicine for
erectile dysfunction.
2.
BEFORE YOU TAKE CIALIS
Do not take CIALIS
-
if you are allergic (hypersensitive) to tadalafil or any of the other ingredients of CIALIS.
-
if you are taking any form of organic nitrate or nitric oxide donors such as amyl nitrite. This is a
group of medicines (“nitrates”) used in the treatment of angina pectoris (“chest pain”). CIALIS has
been shown to increase the effects of these medicines. If you are taking any form of nitrate or are
unsure tell your doctor.
-
if you have serious heart disease or have had a recent heart attack.
-
if you have had a recent stroke
-
if you have low blood pressure or uncontrolled high blood pressure.
- if you have ever had loss of vision because of non-arteritic anterior ischemic optic neuropathy
(NAION), a condition sometimes described as “stroke of the eye”.
75
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to take CIALIS
Take special care with CIALIS
Be aware that sexual activity carries a possible risk to patients with heart disease because it puts an
extra strain on your heart. If you have a heart problem you should tell your doctor.
The following are reasons why CIALIS may also not be suitable for you. If any of them apply to you,
talk to your doctor before you take the medicine:
-
You have sickle cell anaemia (an abnormality of red blood cells), multiple myeloma (cancer of
the bone marrow), leukaemia (cancer of the blood cells) or any deformation of your penis.
-
You have a severe kidney problem.
It is not known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-
nerve-sparing prostatectomy.
If you experience sudden decrease or loss of vision, stop taking CIALIS and contact your doctor
immediately.
CIALIS is not intended for use by women or by adolescents under the age of 18.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicine, including
medicines obtained without prescription, because they might interact.
This is particularly important if you are treated with nitrates as you should not take CIALIS if you are
taking these medicines.
A type of medicine called an alpha blocker is sometimes used to treat high blood pressure and
enlarged prostate. Tell your doctor if you are being treated for either of these conditions or if you take
other medicines to treat high blood pressure.
If you are taking medicines that can inhibit an enzyme called CYP3A4 (for example ketoconazole or
protease inhibitors for treatment of HIV) the frequency of side effects might increase.
Do not take CIALIS with other medicines if your doctor tells you that you may not.
You should not use CIALIS together with any other treatments for erectile dysfunction.
Taking CIALIS with food and drink
You may take CIALIS with or without food.
Information on the effect of alcohol is in section 3.
Driving and using machines
Some men taking CIALIS in clinical studies have reported dizziness. Check carefully how you react to
the medicines before driving or using any machinery.
Important information about some of the ingredients of CIALIS:
CIALIS contains lactose. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicinal product.
3.
HOW TO TAKE CIALIS
Always take CIALIS exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
76
-
You have a serious liver problem.
The recommended starting dose is one 10 mg tablet before sexual activity. If the effect of this dose is
too weak your doctor may increase the dose to 20 mg. CIALIS tablets are for oral use. Swallow the
tablet whole with some water. You may take CIALIS with or without food.
You may take a CIALIS tablet at least 30 minutes before sexual activity. CIALIS may still be effective
up to 36 hours after taking the tablet. It is important to note that CIALIS does not work if there is no
sexual stimulation. You and your partner will need to engage in foreplay, just as you would if you
were not taking a medicine for erectile dysfunction.
Drinking alcohol may affect your ability to get an erection. Drinking alcohol may temporarily lower
your blood pressure. If you have taken or are planning to take CIALIS, avoid excessive drinking
(blood alcohol level of 0.08% or greater), since this may increase the risk of dizziness when standing
up.
You should NOT take CIALIS more than once a day. CIALIS 10 mg and 20 mg is intended for use
prior to anticipated sexual activity and is not recommended for continuous daily use.
If you take more CIALIS than you should
Tell 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, CIALIS can cause side effects, although not everybody gets them. These effects are
normally mild to moderate in nature.
In this leaflet, when a side effect is described as “very common” this means that it has been reported in
at least 1 in 10 patients taking the medicine. When a side effect is described as “common” this means
that it has been reported in more than 1 in every 100 patients but less than 1 in every 10 patients. When
a side effect is described as “uncommon”, this means it has been reported in more than 1 in every 1,000
patients, but less than 1 in every 100 patients. When a side effect is described as “rare”, this means it
has been reported in more than 1 in every 10,000 patients, but less than 1 in every 1,000 patients.
Very commonly reported side effect in patients taking CIALIS were headache.
Commonly reported side effects in patients taking CIALIS include back pain, muscle aches, facial
flushing, nasal congestion, dizziness and indigestion.
Uncommon side effects are allergic reactions including rashes, abdominal pain, reflux, blurred vision,
eye pain, increased sweating, pounding heartbeat sensation, a fast heart rate, high blood pressure, low
blood pressure and chest pain. In case of chest pain occurring during or after sexual activity you
should NOT use nitrates but you should seek immediate medical assistance.
Rare side effects in patients taking CIALIS include fainting, seizures and passing memory loss,
swelling of the eyelids, red eyes, sudden decrease or loss of hearing, hives and nose bleeds.
In rare instances it is possible that a prolonged and possibly painful erection may occur after taking
CIALIS. If you have such an erection, which lasts continuously for more than 4 hours, you should
contact a doctor immediately.
Heart attack and stroke have also been reported rarely in men taking CIALIS. Most, but not all of
these men had known heart problems before taking this medicine. It is not possible to determine
whether these events were directly related to CIALIS.
77
Partial, sudden, temporary, or permanent decrease or loss of vision in one or both eyes has been rarely
reported.
Some additional side effects have been reported in men taking CIALIS at an estimated frequency of
rare that were not seen in clinical trials. These include migraine, swelling of the face, serious skin
rashes, some disorders affecting blood flow to the eyes, irregular heartbeats, angina and sudden
cardiac death. Sudden decrease or loss of hearing has been reported.
Effects were seen in one animal species that might indicate impairment of fertility. Subsequent studies
in man suggest that this effect is unlikely in humans, although 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.
5.
HOW TO STORE CIALIS
Keep out of the reach and sight of children.
Do not use CIALIS 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 CIALIS contains
The active substance is tadalafil. Each tablet contains 10 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), talc.
What CIALIS looks like and contents of the pack
CIALIS 10 mg comes as light yellow film-coated tablets. They are in the shape of almonds and have
"C 10" marked on one side.
Cialis 10 mg is available in blister packs containing 4 tablets.
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.
78
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
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε
Τηλ: +30 210 629 4600
Polska
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
79
PACKAGE LEAFLET : INFORMATION FOR THE USER
CIALIS 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 CIALIS is and what it is used for
2.
Before you take CIALIS
4.
Possible side effects
5
How to store CIALIS
6.
Further information
1.
WHAT CIALIS IS AND WHAT IT IS USED FOR
CIALIS is a treatment for men with erectile dysfunction. This is when a man cannot get, or keep a
hard, erect penis suitable for sexual activity.
CIALIS belongs to a group of medicines called phosphodiesterase type 5 inhibitors. Following sexual
stimulation CIALIS works by helping the blood vessels in your penis to relax, allowing the flow of
blood into your penis. The result of this is improved erectile function. CIALIS will not help you if you
do not have erectile dysfunction.
It is important to note that CIALIS does not work if there is no sexual stimulation. You and your
partner will need to engage in foreplay, just as you would if you were not taking a medicine for
erectile dysfunction.
2.
BEFORE YOU TAKE CIALIS
Do not take CIALIS
-
if you are allergic (hypersensitive) to tadalafil or any of the other ingredients of CIALIS.
-
if you are taking any form of organic nitrate or nitric oxide donors such as amyl nitrite. This is a
group of medicines (“nitrates”) used in the treatment of angina pectoris (“chest pain”). CIALIS
has been shown to increase the effects of these medicines. If you are taking any form of nitrate
or are unsure tell your doctor.
-
if you have serious heart disease or have had a recent heart attack.
-
if you have had a recent stroke.
-
if you have low blood pressure or uncontrolled high blood pressure.
-
if you have ever had loss of vision because of non-arteritic anterior ischemic optic neuropathy
(NAION), a condition described as “stroke of the eye”.
80
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to take CIALIS
Take special care with CIALIS
Be aware that sexual activity carries a possible risk to patients with heart disease because it puts an
extra strain on your heart. If you have a heart problem you should tell your doctor.
The following are reasons why CIALIS may also not be suitable for you. If any of them apply to you,
talk to your doctor before you take the medicine:
-
You have sickle cell anaemia (an abnormality of red blood cells), multiple myeloma (cancer of
the bone marrow), leukaemia (cancer of the blood cells) or any deformation of your penis.
-
You have a severe kidney problem
It is not known if CIALIS is effective in patients who have undergone pelvic surgery or radical non-
nerve-sparing prostatectomy.
If you experience sudden decrease or loss of vision, stop taking CIALIS and contact your doctor
immediately.
CIALIS is not intended for use by women or by adolescents under the age of 18.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without prescription, because they might interact.
This is particularly important if you are treated with nitrates as you should not take CIALIS if you are
taking these medicines.
A type of medicine called an alpha blocker is sometimes used to treat high blood pressure and
enlarged prostate. Tell your doctor if you are being treated for either of these conditions or if you take
other medicines to treat high blood pressure.
If you are taking medicines that can inhibit an enzyme called CYP3A4 (for example ketoconazole or
protease inhibitors for treatment of HIV) the frequency of side effects might increase.
Do not take CIALIS with other medicines if your doctor tells you that you may not.
You should not use CIALIS together with any other treatments for erectile dysfunction.
Taking CIALIS with food and drink
You may take CIALIS with or without food.
Information on the effect of alcohol is in section 3.
Driving and using machines
Some men taking CIALIS in clinical studies have reported dizziness. Check carefully how you react to
the medicines before driving or using any machinery.
Important information about some of the ingredients of CIALIS:
CIALIS contains lactose. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicinal product.
3.
HOW TO TAKE CIALIS
Always take CIALIS exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
81
-
You have a serious liver problem.
The recommended starting dose is one 10 mg tablet before sexual activity. If the effect of this dose is
too weak your doctor may increase the dose to 20 mg. CIALIS tablets are for oral use. Swallow the
tablet whole with some water. You may take CIALIS with or without food.
You may take a CIALIS tablet at least 30 minutes before sexual activity. CIALIS may still be effective
up to 36 hours after taking the tablet. It is important to note that CIALIS does not work if there is no
sexual stimulation. You and your partner will need to engage in foreplay, just as you would if you
were not taking a medicine for erectile dysfunction.
Drinking alcohol may affect your ability to get an erection. Drinking alcohol may temporarily lower
your blood pressure. If you have taken or are planning to take CIALIS, avoid excessive drinking
(blood alcohol level of 0.08% or greater), since this may increase the risk of dizziness when standing
up.
You should NOT take CIALIS more than once a day. CIALIS 10 mg and 20 mg is intended for use
prior to anticipated sexual activity and is not recommended for continuous daily use.
If you take more CIALIS than you should
Tell 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, CIALIS can cause side effects, although not everybody gets them. These effects are
normally mild to moderate in nature.
In this leaflet, when a side effect is described as “very common” this means that it has been reported in
at least 1 in 10 patients taking the medicine. When a side effect is described as “common” this means
that it has been reported in more than 1 in every 100 patients but less than 1 in every 10 patients. When
a side effect is described as “uncommon”, this means it has been reported in more than 1 in every 1,000
patients, but less than 1 in every 100 patients. When a side effect is described as “rare”, this means it
has been reported in more than 1 in every 10,000 patients, but less than 1 in every 1,000 patients.
Very commonly reported side effect in patients taking CIALIS were headache.
Commonly reported side effects in patients taking CIALIS include back pain, muscle aches, facial
flushing, nasal congestion, dizziness and indigestion.
Uncommon side effects are allergic reactions including rashes, abdominal pain, reflux, blurred vision,
eye pain, increased sweating, pounding heartbeat sensation, a fast heart rate, high blood pressure, low
blood pressure and chest pain. In case of chest pain occurring during or after sexual activity you
should NOT use nitrates but you should seek immediate medical assistance.
Rare side effects in patients taking CIALIS include fainting, seizures and passing memory loss,
swelling of the eyelids, red eyes, sudden decrease or loss of hearing, hives and nose bleeds.
In rare instances it is possible that a prolonged and possibly painful erection may occur after taking
CIALIS. If you have such an erection, which lasts continuously for more than 4 hours, you should
contact a doctor immediately.
Heart attack and stroke have also been reported rarely in men taking CIALIS. Most, but not all of
these men had known heart problems before taking this medicine. It is not possible to determine
whether these events were directly related to CIALIS.
82
Partial, sudden, temporary, or permanent decrease or loss of vision in one or both eyes has been rarely
reported.
Some additional side effects have been reported in men taking CIALIS at an estimated frequency of
rare that were not seen in clinical trials. These include migraine, swelling of the face, serious skin
rashes, some disorders affecting blood flow to the eyes, irregular heartbeats, angina, and sudden
cardiac death.
Effects were seen in one animal species that might indicate impairment of fertility. Subsequent studies
in man suggest that this effect is unlikely in humans, although 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.
5.
HOW TO STORE CIALIS
Keep out of the reach and sight of children.
Do not use CIALIS 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 CIALIS 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), talc.
What CIALIS looks like and contents of the pack
CIALIS 20 mg comes as yellow film-coated tablets. They are in the shape of almonds and have "C 20"
marked on one side.
CIALIS 20 mg is available in blister packs containing 2, 4, 8, 10 or 12 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.
83
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
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε
Τηλ: +30 210 629 4600
Polska
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
84
Source: European Medicines Agency
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