Chemical y, tadalafil is pyrazino[1', 2':1, 6]pyrido[3, 4-b]indole-1, 4-dione,
6-(1, 3-benzodioxol-5-yl)-2, 3, 6, 7, 12, 12a-hexahydro-2-methyl-, (6R, 12aR)-.
Tadalafil has the empirical formula C22H19N3O4 representing a molecular
weight of 389.41. Tadalafil is a crystal ine solid that is practical y insoluble in water and very slightly soluble in ethanol. The CAS number for tadalafil is 171596-29-5.
Tadalafil has the fol owing structural formula:
CIALIS 20 mg tablets are yel ow, film coated, almond shaped tablets for
oral administration, marked "C 20" on one side. CIALIS 10 mg tablets are
light yel ow, film coated, almond shaped tablets for oral administration,
marked "C 10" on one side. CIALIS 5 mg tablets are light yel ow, film coated, almond shaped tablets for oral administration, marked "C 5" on one side. CIALIS 2.5 mg tablets are light orange-yel ow, film coated, almond
shaped tablets for oral administration, marked "C 2 ½" on one side. The
active ingredient in CIALIS tablets is tadalafil. CIALIS tablets also contain
the fol owing excipients: croscarmel ose sodium, hydroxypropylcel ulose,
hypromel ose, lactose, magnesium stearate, cel ulose - microcrystal ine,
sodium lauryl sulfate, talc - purified, titanium dioxide and glycerol triacetate.
CIALIS 10 mg and 20 mg tablets also contain iron oxide yel ow CI77492.
CIALIS 5 mg tablets also contain Opadry I complete film coating system
Y-30-12863-A Yel ow. Cialis 2.5mg tablets also contain Opadry I complete
film coating system 32K12891 Yel ow.PHARMACOLOGY
Tadalafil is a 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 ef ect in the absence of
sexual stimulation. Studies in vitro
have shown that tadalafil inhibits PDE5
more potently than other PDEs. PDE5 is an enzyme found in the corpus
cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal
muscle, platelets, kidney, lung and cerebel um. Tadalafil is >10,000-fold more
potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes which
are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle
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. Additional y, 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 >9,000-fold more potent
for PDE5 than for PDE8, 9 and 10 and 14-fold more potent for PDE5 than
for PDE11. The tissue distribution and physiological ef ects of the inhibition of
PDE8 through PDE11 have not been elucidated.
Studies of CIALIS on vision – In a study to assess the ef ects of tadalafil on
vision, no impairment of colour discrimination (blue/green) was detected
using the Farnsworth-Munsel 100-hue test. This finding is consistent with
should be avoided (see CONTRAINDICATIONS).
the low affinity of tadalafil for PDE6 compared to PDE5. In addition, no ef ects
Renal Impairment – In subjects with renal insufficiency, including those on
were observed on visual acuity, electroretinograms, intraocular pressure or
haemodialysis, tadalafil exposure (AUC) was higher than in healthy subjects.
pupil ometry. Across al clinical studies, reports of changes in colour vision
Therefore, the recommended starting dose of tadalafil in patients with mild
were rare (see ADVERSE EFFECTS).
or moderate renal impairment is 10 mg. For patients with severe renal
Studies of CIALIS on blood pressure and heart rate – Tadalafil administered
impairment 10 mg is the maximum recommended dose (see DOSAGE and
to healthy subjects produced no significant dif erence compared to placebo
in supine systolic and diastolic blood pressure (mean maximal decrease
A single dose study in 8 men suf ering from End Stage Renal Disease
of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood
who were stable on haemodialysis showed 3-4 fold increase in AUC and
pressure (mean maximal decrease of 0.2/4.6 mm Hg, respectively) and no
2-2.5 fold increase in Cmax in tadalafil levels. The half-life of the drug is also
significant change in heart rate. Larger ef ects were recorded among subjects prolonged.
receiving concomitant nitrates (see CONTRAINDICATIONS).
Hepatic Impairment – Tadalafil exposure (AUC) in subjects with mild and
Studies on Spermatogenesis – Three studies were conducted in men
moderate hepatic impairment (Child-Pugh Class A and B) is comparable to
to assess the potential ef ect on spermatogenesis of tadalafil 10 mg
exposure in healthy subjects. No control ed data are available in patients with
(one 6-month study) and 20 mg (one 6-month and one 9-month study)
severe hepatic impairment (Child-Pugh Class C). Once-a-day administration
administered daily. There were no adverse ef ects on sperm morphology
has not been evaluated in patients with hepatic insufficiency. If tadalafil is
or sperm motility in any of the three studies. In the study of 10 mg tadalafil
prescribed, a careful individual benefit/risk evaluation should be undertaken
for 6 months and the study of 20 mg tadalafil for 9 months, results showed
by the prescribing physician.
a decrease in mean sperm concentrations relative to placebo. This ef ect
Patients with Diabetes - Tadalafil exposure (AUC) in patients with diabetes
was not seen in the study of 20 mg tadalafil taken for 6 months. In all
was approximately 19% lower than the AUC value for healthy subjects. This
3 studies there were no statistical y significant dif erences between the
dif erence in exposure does not warrant a dose adjustment.
placebo and tadalafil groups for mean total sperm counts. In addition there
was no adverse ef ect on mean concentrations of reproductive hormones, testosterone, luteinising hormone or fol icle stimulating hormone with either
On-Demand Dosing for the Treatment of Erectile Dysfunction
10 or 20 mg of tadalafil compared to placebo.
Tadalafil when taken on demand up to once daily, is ef ective in improving
erectile function in men with erectile dysfunction (ED). In clinical studies assessing patients' ability to engage in successful and satisfying sexual
Absorption – Tadalafil is rapidly absorbed after oral administration and the
activity, tadalafil demonstrated highly statistical y significant improvement
mean maximum observed plasma concentration (Cmax) is achieved at a
compared to placebo. Additional y, partners of patients on tadalafil had
median time of 2 hours after dosing. There is no clinical y relevant ef ect of
statistical y significant greater satisfaction with sexual activity compared to
food on the rate and extent of absorption of tadalafil, thus tadalafil may be
partners of patients on placebo. Tadalafil at doses of 2 to 100 mg has been
taken with or without food. The time of dosing (morning versus evening)
evaluated in 16 clinical studies involving 3250 patients. Tadalafil 10 mg and/
has no clinical y relevant ef ects on the rate and extent of absorption. The
or 20 mg, taken on demand up to once daily, was compared to placebo in
absolute bioavailability of oral tadalafil has not been established. The mean
6 primary efficacy studies (5 in a general ED population, 1 in patients with
bioavailability of the tadalafil 20 mg tablet has been estimated to be 88%
diabetes). Seven hundred and twenty four (724) patients received tadalafil
relative to an oral suspension dosage form.
10 mg or 20 mg and 379 patients received placebo in these randomised,
Distribution – The mean volume of distribution after oral dosing is
double blinded, paral el group studies. Patients were free to choose the time
approximately 63 L. At therapeutic concentrations, 94% of tadalafil in
interval between dose administration and the time of sexual attempts. Food
plasma is bound to proteins. Protein binding is not af ected by impaired renal
and alcohol intake were not restricted. The studies were designed in this
function. Less than 0.0005% of the administered dose appears in the semen
manner in order to al ow for convenience and dosing flexibility for the patient
of healthy subjects.
and partner. Several assessment instruments were used to evaluate the
Metabolism – Tadalafil is metabolised mainly (>80%) by the cytochrome
ef ect of tadalafil on erectile function. Global Assessment Questions (GAQ)
P450 (CYP) 3A4 isoform, with minor contributions by CYPs 2C8, 2C9,
were asked to determine whether the treatment improved patients' erections.
2C19 and 2D6 (<20% col ectively). The major circulating metabolite is the
During clinical studies, patients and partners completed sexual encounter
methylcatechol glucuronide. This metabolite is at least 13,000-fold less
profile (SEP) diaries assessing erectile function and sexual satisfaction of
potent than tadalafil for PDE5. Consequently, it is not expected to be clinical y each sexual attempt. The International Index of Erectile Function (I EF), a
active at observed metabolite concentrations.
recall questionnaire, was also completed by patients. The IIEF provides global
Elimination – The mean oral clearance for tadalafil is 2.5 L/hr and the mean
measures of erectile function and sexual satisfaction, as well as severity of ED.
half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly
In al primary efficacy studies, tadalafil demonstrated consistent and statistical y
as inactive metabolites, mainly in the faeces (approximately 61% of the dose)
significant improvement compared to placebo in al primary and secondary
and to a lesser extent in the urine (approximately 36% of the dose).
endpoints evaluated. In each primary efficacy study, a significant treatment
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time
ef ect was declared only if there was a statistical y significant improvement on
and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases
al three co-primary measures: 1) the I EF Erectile Function Domain; 2) SEP
proportional y with dose. Steady-state plasma concentrations are attained
Question 2 (assessing the ability to penetrate the partner's vagina); and 3) SEP
within 5 days of once-daily dosing.
Question 3 (assessing the ability to maintain the erection). The treatment ef ect
Pharmacokinetics determined with a population approach in patients with
did not diminish over time. Overal , tadalafil consistently showed efficacy in a
erectile dysfunction are similar to pharmacokinetics in subjects without
broad and representative population that included patients with ED of various
severities (mild, moderate, severe), etiologies (including patients with diabetes),
Table 1: Summary of Geometric Mean (CV%) Single Dose
ages (21 to 86 years), ethnicities and durations of ED. In the five primary
Pharmacokinetic Parameters of tadalafil (20 mg) in Healthy Volunteers
efficacy studies of general populations, 81% of patients reported that tadalafil 20 mg improved their erections compared to 35% of patients on placebo. Also,
patients with ED in al severity categories reported improved erections while
taking tadalafil 20 mg (86%, 83% and 72% for mild, moderate and severe,
respectively) compared to patients on placebo (45%, 42% and 19% for mild,
moderate and severe respectively). Tadalafil showed statistical y significant improvement in patients' ability to achieve an erection sufficient for sexual
ª Median and range
intercourse and maintain the erection for successful intercourse as measured
Pharmacokinetics in Special Populations
by the SEP diaries. In the primary efficacy studies, 75% of intercourse attempts were successful in patients taking tadalafil 20 mg compared to 32% of patients
Elderly – Healthy elderly subjects (65 years or over) had a lower clearance of
on placebo. This finding was confirmed by partner SEP responses. Tadalafil
tadalafil, resulting in a half life of 22 hours and 25% higher exposure (AUC),
also demonstrated statistical y significant improvement in erectile function as
relative to healthy subjects aged 19 to 45 years (half life of 16-17 hours). This
measured by the I EF Erectile Function Domain. Additional y, in the primary
ef ect does not appear to warrant a dose adjustment (see DOSAGE AND
efficacy studies, approximately 60% of patients taking tadalafil 20 mg achieved
ADMINISTRATION – Elderly Patients). The half-life of tadalafil in the elderly
normal erectile function during treatment. Patients with ED in al severity
increases the period after the last dose of CIALIS during which nitrates
categories improved into the normal range (defined by I EF).
Patient Confidence and Sexual Satisfaction – The I EF also measures
- patients with a myocardial infarction within the last 90 days
patients' confidence that they can attain and keep an erection sufficient
- patients with unstable angina or angina occurring during sexual intercourse
for sexual intercourse. Tadalafil statistical y significantly improved patient
- patients with New York Heart Association Class 2 or greater heart failure in
confidence. Analysis of the Intercourse Satisfaction and Overal Satisfaction
the last 6 months
domains of the I EF showed that tadalafil treatment provided statistical y
- patients with uncontrol ed arrhythmias, hypotension (<90/50 mm Hg), or
significant enhancement of sexual satisfaction measured by both domains.
uncontrol ed hypertension
Additional y, tadalafil improved the proportion of sexual encounters that were
- patients with a stroke within the last 6 months.
satisfying for both the patient and the partner.
Tadalafil should not be used in patients with a known hypersensitivity to
Efficacy in ED Patients with Diabetes Mel itus – Tadalafil is ef ective in treating
tadalafil or to any ingredient of the tablet.
ED in patients with diabetes. Patients with diabetes (n=451) were included in
al primary efficacy studies, one of which specifical y assessed tadalafil only in ED patients with Type 1 or Type 2 diabetes. Tadalafil produced statistical y
Caution should be exercised when prescribing CIALIS to patients with
significant improvement in erectile function and sexual satisfaction. In these
severe hepatic insufficiency (Child-Pugh Class C) or to those taking CYP3A4
studies, 68% of patients with diabetes taking tadalafil 20 mg reported
inhibitors or HIV protease inhibitors.
Once-a-day administration has not been evaluated extensively in patients
Period of Responsiveness – The diary data from 11 previous efficacy
with hepatic insufficiency. If tadalafil is prescribed, a careful individual benefit/
studies in the general ED population was combined to define the period of
risk evaluation should be undertaken by the prescribing physician.
responsiveness. There were 321, 1143, and 638 patients in the 10 mg, 20
The evaluation of erectile dysfunction should include a determination of
mg tadalafil and placebo group respectively. The response appeared as early
potential underlying causes and the identification of appropriate treatment
as <1 hour. At 24 hours, 71% & 72% of attempts at sexual intercourse were
fol owing an appropriate medical assessment.
successful with 10 mg (n=76) and 20 mg (n=366) tadalafil respectively. The
Physicians should consider the potential cardiac risk of sexual activity in
success rate at 36 hours was 72% and 75% with 10 mg (n=34) and 20 mg
patients with preexisting cardiovascular disease. Patients who experience
(n=129) tadalafil respectively. The success rate with placebo was 44% (n=135)
symptoms upon initiation of sexual activity should be advised to refrain from
and 47% (n=46) at 24 and 36 hours post-dose respectively. Therefore, tadalafil
further sexual activity and should report the episode to their physician.
demonstrated statistical y significant improvement in erectile function and the
As with other PDE5 inhibitors, tadalafil has systemic vasodilatory properties
ability to have successful sexual intercourse up to 36 hours fol owing dosing,
that may result in mild and transient decreases in blood pressure. Prior
as wel as patients' ability to attain and maintain erections for successful
to prescribing CIALIS, physicians should careful y consider whether their
intercourse compared to placebo as early as 16 minutes fol owing dosing.
patients with underlying cardiovascular disease could be af ected adversely
Once-a-Day Dosing for the Treatment of Erectile Dysfunction
by vasodilatory ef ects. Tadalafil potentiates the hypotensive ef ect of nitrates. Therefore, coadministration of CIALIS and nitrates is contraindicated (see
Tadalafil at doses of 2.5, 5, and 10 mg taken once a day has been evaluated
CONTRAINDICATIONS). Tadalafil also potentiates the ef ect of some classes
in 3 clinical studies involving 853 patients of various ages (range 21-82 years)
of antihypertensive medications, and this may be clinical y important in
and ethnicities, with erectile dysfunction of various severities (mild, moderate,
some individuals. When initiating daily treatment with tadalafil, appropriate
severe) and etiologies. In the two primary efficacy studies of general
clinical considerations should be given to a possible dose adjustment of the
populations, 76 and 85% of patients reported that tadalafil 5 mg taken once
antihypertensive therapy. (see PRECAUTIONS – Potential for CIALIS to Af ect
a day improved their erections as compared to 29 and 30% with placebo.
Other Drugs – Antihypertensive Agents).
Also, patients with erectile dysfunction in al severity categories reported improved erections while taking tadalafil once a day. In the primary efficacy
Specific studies examining potential withdrawal ef ects from daily use have
studies, 62 and 69% of intercourse attempts in the general population
not been conducted. Rebound ef ects on blood pressure have not been
studies were successful in tadalafil 5 mg-treated patients as compared to 34
observed after fol ow-up assessments at 2 weeks and 4 weeks fol owing
and 39% with placebo. Tadalafil 5 mg significantly improves erectile function
cessation of up to 1 year of chronic daily treatment of CIALIS. Blood pressure
over the 24-hour period between the doses.
was not specifical y monitored leading up to or between the 2 and 4 weeks posttreatment assessments. Based upon the limited clinical data examining
withdrawal ef ects, it is recommended that physicians continue monitoring
CIALIS is indicated for the treatment of erectile dysfunction in adult males.
the cardiovascular status, including blood pressure changes, of their patients
CIALIS is not indicated for use by women.
after discontinuation of CIALIS.
Physicians should advise patients to stop taking PDE5 inhibitors, including
Nitrates and tadalafil must not be used concomitantly. Co-administration of
CIALIS, and seek prompt medical attention in the event of sudden decrease
tadalafil with nitric oxide donors, organic nitrates or organic nitrites in any form
or loss of hearing. These events, which may be accompanied by tinnitus and
either regularly or intermittently is contraindicated. Drugs which must not be
dizziness, have been reported in temporal association to the intake of PDE5
used concomitantly include, but are not limited to, glyceryl trinitrate (injection,
inhibitors, including CIALIS. It is not possible to determine whether these
tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, events are related directly to the use of PDE5 inhibitors or to other factors nicorandil or organic nitrates in any form. In clinical studies, tadalafil was
(see ADVERSE EFFECTS).
shown to potentiate the hypotensive effects of both acute and chronic nitrate
Caution should be exercised when prescribing CIALIS to patients who are
administration. This is thought to result from the combined effects of nitrates
taking alpha blockers, such as doxazosin, as simultaneous administration
and tadalafil on the nitric oxide/cGMP pathway.
may lead to symptomatic hypotension in some patients (See PRECAUTIONS
Administration of tadalafil to patients who are using any form of organic nitrate
– Potential for CIALIS to Af ect Other Drugs). The safety and efficacy of
is contraindicated. In a patient prescribed CIALIS where nitrate administration
combinations of tadalafil and other PDE5 inhibitors or treatments for erectile
is deemed medically necessary in a life-threatening situation, at least 48 hours
dysfunction have not been studied. Therefore, the use of such combinations
in most patients and 4-5 days in the elderly (approximately 4-5 half lives)
is not recommended.
should have elapsed after the last dose of CIALIS before nitrate administration
Priapism has been reported with PDE5 inhibitors, including tadalafil. Patients
is considered. In such circumstances, nitrates should only be administered
who experience erections lasting 4 hours or more should be instructed to
under close medical supervision with appropriate haemodynamic monitoring
seek immediate medical assistance. If priapism is not treated immediately,
(see PRECAUTIONS- Interactions with Other Drugs).
penile tissue damage and permanent loss of potency may result.
Tadalafil is contraindicated in men for whom sexual intercourse is inadvisable
Tadalafil should be used with caution in patients who have conditions that
due to unstable cardiovascular disease (e.g. patients with unstable angina
might predispose them to priapism (such as sickle cel anaemia, multiple
and severe congestive heart failure) [see PRECAUTIONS]. The possibility of
myeloma, or leukaemia), or in patients with anatomical deformation of the
undiagnosed cardiovascular disorders in men with erectile dysfunction should penis (such as angulation, cavernosal fibrosis or Peyronie's disease).
be considered before prescribing tadalafil.
In a clinical pharmacology study, administration of tadalafil 10 mg to patients
Tadalafil is contraindicated in patients who have loss of vision in one eye
with moderate renal failure (creatinine clearance = 31 to 50 mL/min) was
because of nonarteritic anterior ischaemic optic neuropathy (NAION),
determined to be safe but appeared to be less wel tolerated in terms of back
regardless of whether this episode was in connection or not with previous
pain than in patients with mild renal failure (creatinine clearance = 51 to 80
PDE5 inhibitor exposure (see PRECAUTIONS).
mL/min) and in healthy subjects. In a single dose, pharmacodynamic study of
The fol owing groups of patients with cardiovascular disease were not
8 patients with End Stage Renal Disease who were stable on haemodialysis,
included in clinical trials and the use of tadalafil is therefore contraindicated:
the reported adverse ef ects included headache, dizziness, and somnolence.
Tadalafil should be prescribed with caution for patients with creatinine
CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.
clearance < 50 mL/min.
Potential for Other Drugs to Affect CIALIS:
Due to increased tadalafil exposure (AUC), limited clinical experience, and the
Tadalafil is principal y metabolised by CYP3A4. A selective inhibitor of
lack of ability to influence clearance by dialysis, once-a-day dosing of tadalafil
CYP3A4, ketoconazole (400 mg daily), increased tadalafil single-dose
is not recommended in patients with severe renal impairment.
exposure (AUC) by 312% and Cmax by 22%, and ketaconazole (200 mg
Physicians should advise patients to stop use of all PDE5 inhibitors, including
daily), increased tadalafil single-dose exposure (AUC) by 107%, and Cmax by
CIALIS, and seek medical attention in the event of a sudden loss of vision
15% relative to the AUC and Cmax values for tadalafil (10 mg) alone.
in one or both eyes (see CONTRAINDICATIONS). Such an event may be a
Ritonavir (200 mg twice daily), an inhibitor of CYP3A4, 2C9, 2C19, and 2D6,
sign of non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of
increased tadalafil single-dose exposure (AUC) by 124% with no change
decreased vision, including permanent loss of vision that has been reported
rarely postmarketing in temporal association with the use of all PDE5 inhibitors.
max. Although specific interactions have not been studied, other HIV
protease inhibitors such as saquinavir, and other CYP3A4 inhibitors, such
It is not possible to determine whether these events are related directly to the
as erythromycin, clarithromycin, itraconazole and grapefruit juice should be
use of PDE5 inhibitors or to other factors (see ADVERSE EFFECTS - Adverse
co-administered with caution because they would be expected to increase
events identified from spontaneous post marketing surveillance).
plasma concentrations of tadalafil. A selective CYP3A4 inducer, rifampicin
Ef ects on Fertility
(600 mg daily), reduced tadalafil single-dose exposure (AUC) by 88%, and
There were no ef ects on fertility, reproductive performance or reproductive
Cmax by 46% relative to the AUC and Cmax values for tadalafil (10 mg) alone.
organ morphology in male or female rats given oral doses of tadalafil
This reduced exposure can be anticipated to decrease the efficacy of once-
up to 400 mg/kg/day (systemic exposure ca 13 (males) or 25 (females)
a-day-dosed tadalafil; the magnitude of decreased efficacy is unknown. It
times that expected at the maximum recommended dose of 20 mg taken
can be expected that concomitant administration of other CYP3A4 inducers
once daily, based on AUC for unbound drug at steady state). However,
such as phenobarbitone, phenytoin and carbamazepine would also decrease
regression of the seminiferous tubular epithelium of the testes resulting
plasma concentrations of tadalafil.
in oligospermia or aspermia in the epididymides was observed in dogs
Studies with the CYP3A4 probe substrates midazolam with tadalafil 10 mg and
treated for 6 or 12 months with oral tadalafil doses ≥25 mg/kg/day. The
lovastatin with tadalafil 20 mg showed little alteration in the kinetics suggesting
no-observed-ef ect level for these ef ects in the 6-month dog study was 10
that tadalafil is unlikely to have interactions with CYP3A4 substrates.
mg/kg/day. At this dose, systemic exposure to tadalafil, based on unbound
Antacids (magnesium hydroxide/aluminium hydroxide) – Simultaneous
drug concentrations, was similar to that expected in humans taking the
administration of an antacid (magnesium hydroxide/aluminium hydroxide) and
maximum recommended dose of 20 mg CIALIS daily. Similar findings were
tadalafil reduced the apparent rate of absorption of tadalafil without altering
not observed in rats and mice (see Pharmacodynamics).
exposure (AUC) to tadalafil (10 mg).
H2 antagonists – An increase in gastric pH resulting from administration of nizatidine had no significant ef ect on tadalafil (10 mg) pharmacokinetics.
Pregnancy category B1.
Tadalafil is not intended for use by women.
Potential for CIALIS to Affect Other Drugs
Studies in rats have shown that tadalafil and/or its metabolites cross the
Nitrates – In clinical pharmacology studies, tadalafil 10 mg was shown to
placenta and distribute to the foetus. No evidence of embryofoetal toxicity
potentiate the hypotensive ef ects of nitrates. Therefore, administration
or teratogenicity was observed in pregnant rats or mice given oral doses
of tadalafil to patients who are using any form of organic nitrate is
of tadalafil up to 1000 mg/kg/day. These doses were associated with
contraindicated. A placebo-control ed study was conducted to assess the
systemic exposure to tadalafil ca
12-14-fold that expected at the maximum
degree of interaction between nitroglycerine and tadalafil. One hundred
recommended dose of 20 mg taken once daily, based on AUC for unbound
and fifty subjects received daily doses of tadalafil 20 mg for 7 days. On
drug at steady state. Increased postnatal pup mortality was observed in
the 7th day, 0.4 mg sublingual nitroglycerine was given at various times
rats after oral treatment with tadalafil doses ≥60 mg/kg/day during gestation
fol owing the daily dose of tadalafil. This interaction lasted for more than
and lactation. The no-ef ect dose of 30 mg/kg/day was associated with
24 hours and was no longer detectable when 48 hours had elapsed (see
systemic exposure ca
10-fold that expected in humans at the maximum
recommended dose of 20 mg tadalafil taken once daily, based on AUC for
Recreational Drugs cal ed "poppers" or "amyl" – Due to the known interaction
unbound drug at steady state.
between tadalafil and nitrates or other nitric oxide donors on nitrogen
There are no studies of tadalafil in pregnant women.
monoxide/cGMP metabolism, patients must be expressly informed that they should never use recreational drugs cal ed "poppers" or "amyl", typical y
taken through inhalation. These drugs represent various alkyl nitrites including
Tadalafil is not intended for use by women.
amyl nitrite, butyl nitrite and isobutyl nitrite.
Tadalafil and/or its metabolites are excreted in the milk of lactating rats at
Antihypertensive agents – Tadalafil has systemic vasodilatory properties and
concentrations up to 2.4-fold higher than the maximal maternal plasma
may augment the blood pressure lowering ef ects of antihypertensive agents.
concentration. Increased postnatal pup mortality was observed in rats after
Patients should be advised of this possibility. In a clinical pharmacology
treatment with oral tadalafil doses ≥60 mg/kg/day during gestation and
study measuring ambulatory blood pressure, when tadalafil (20 mg) was
lactation (see Use in Pregnancy). There are no human data on the excretion
administered to 17 hypertensive patients treated with angiotensin I receptor
of tadalafil into breast milk or on the safety of tadalafil exposure in infants.
blockers, ambulatory systolic blood pressure fel by 30 mmHg or more in
9 (53%) subjects on tadalafil treatment and in 5 (29%) subjects on placebo
Oral administration of tadalafil at doses of 400 mg/kg/day for up to
treatment, with a maximum fal of 57 mmHg fol owing tadalafil compared
two years in mice resulted in increased development of hepatocel ular
to 37 mmHg fol owing placebo. None of the decreases were associated
adenomas in males but not in females. Tadalafil also caused hepatocel ular
with any hypotensive symptoms. Additional y, in patients taking multiple
microsomal enzyme induction in rodents and it is possible that this could
antihypertensive agents whose hypertension was not wel control ed, greater
lead to an increased incidence of hepatocel ular neoplasms. However,
reductions in blood pressure were observed. These reductions were not
hepatic microsomal enzyme induction is a common non-genotoxic biologic
associated with hypotensive symptoms in the vast majority of patients.
ef ect associated with hepatocel ular tumour formation in rodents and is not
Appropriate clinical advice should be given to patients when they are treated
considered relevant to human cancer risk. The no ef ect dose of 60 mg/kg/
with antihypertensive medications and CIALIS.
day was associated with systemic exposure to tadalafil approximately 5- to
When initiating daily treatment with tadalafil, appropriate clinical
7- fold that expected in men taking the maximum recommended dose of
considerations should be given to a possible dose adjustment of the
20 mg daily, based on unbound drug concentrations.
In other clinical pharmacology studies, tadalafil 10 mg was added to
angiotensin converting enzyme (ACE) inhibitors (enalapril), beta blockers
Tadalafil was not mutagenic or genotoxic in in vitro
bacterial and mammalian cell
(metoprolol) or thiazide diuretics (bendrofluazide). Tadalafil 10 mg and 20
assays, and in in vitro
human lymphocytes and in vivo
rat micronucleus assays.
mg was added to calcium channel blockers (amlodipine) or alpha-blockers
Interactions with Other Medicines
(tamsulosin). In al these studies, tadalafil did not produce a significant
Tadalafil is not expected to cause clinical y significant inhibition or induction
additional reduction in mean systolic or diastolic blood pressure. However,
of the clearance of drugs metabolised by CYP450 isoforms. Studies have
potential y significant blood pressure reductions occurred in some individuals.
confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including
Analysis of phase 3 clinical trial data showed no dif erence in the overall
incidence of adverse events in patients taking tadalafil with or without
Tadalafil was administered to over 4000 subjects (ages 19 to 86 years) during
clinical trials worldwide. Over 230 patients were treated for longer than one
In two clinical pharmacology studies, no significant decreases in blood
year and over 720 patients were treated for over 6 months. In control ed
pressure were observed when tadalafil was co-administered to healthy
phase 2/3 clinical trials, the discontinuation rate due to adverse events in
subjects taking the selective alpha[1A]adrenergic blocker, tamsulosin.
tadalafil-treated patients (1.7%) was not significantly dif erent from placebo-
In three clinical pharmacology studies when tadalafil was co-administered
treated patients (1.1%). In these studies, the adverse events reported with
to healthy subjects taking doxazosin (4-8 mg daily), an alpha-adrenergic
tadalafil were general y mild or moderate, transient and decreased with
blocker, there was an augmentation of the blood-pressure-lowering ef ect
continued dosing. In control ed phase 2/3 clinical trials, the fol owing adverse
of doxazosin. The number of patients with potential y clinical y significant
events were reported.
standing-blood-pressure decreases was greater for the combination. In these
Frequency estimate: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10),
clinical pharmacology studies there were symptoms associated with the
Uncommon (≥ 1/1000 to < 1/100), Rare (≥ 1/10,000 to < 1/1000), Very Rare
decrease in blood pressure including syncope.
(< 1/10,000) and Not known (events not reported in registration trials cannot
Caution is advised when PDE5 inhibitors are coadministered with
be estimated from postmarketing spontaneous reports).
nonselective alpha ( 1)blockers. PDE5 inhibitors, including CIALIS, and
Table 2: Adverse events reported by ≥2% of patients treated with Tadalafil
alpha-adrenergic blocking agents are both vasodilators with blood-pressure-
10-20 mg and more frequent on drug than placebo in phase 3 studies
lowering ef ects. When vasodilators are used in combination, an additive ef ect on blood pressure may be anticipated. In some patients, concomitant
use of these two drug classes can lower blood pressure significantly, which
may lead to symptomatic hypotension (e.g., fainting). Consideration should
be given to the fol owing;
- Patients should be stable on alpha-blocker therapy prior to initiating a PDE5
inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with
concomitant use of PDE5 inhibitors.
- In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors
Musculoskeletal System Back Pain
should be initiated at the lowest recommended dose.
- In those patients already taking an optimized dose of PDE5 inhibitor, alpha-
blocker therapy should be initiated at the lowest dose. Stepwise increase in
alpha-blocker dose may be associated with further lowering of blood pressure
when taking a PDE5 inhibitor.
- Safety of combined use of PDE5 inhibitors and alpha-blockers may be
af ected by other variables, including intravascular volume depletion and
– Common: dizziness
other anti-hypertensive drugs.
– Uncommon: conjunctival
Human platelets contain the PDE5 enzyme system. Tadalafil, in limited
studies, did not af ect platelet function in vivo
. In in vitro
studies tadalafil was
described as eye pain;
shown to potentiate the antiaggregatory ef ect of sodium nitroprusside (a
swel ing of eyelids.
nitric oxide donor).
Alcohol – Tadalafil did not af ect alcohol concentrations, and alcohol did
– Rare: changes in colour
not af ect tadalafil concentrations. At high doses of alcohol (0.7 g/kg), the
addition of tadalafil 20 mg did not induce statistical y significant mean blood
Ear and labyrinth
– Uncommon: sudden
pressure decreases. In some subjects, postural dizziness and orthostatic
decrease or loss of
hypotension were observed. When tadalafil was administered with lower
doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness
(a) Sudden decrease or loss of hearing has been reported in a smal number
occurred with similar frequency to alcohol alone.
of postmarketing and clinical trial cases with the use of al PDE5 inhibitors,
Aspirin – Tadalafil (10 mg) did not potentiate the increase in bleeding time
including tadalafil. In some of the cases, medical conditions and other
caused by aspirin.
factors were reported that may have also played a role in the ear and
Warfarin – In a crossover study, 12 healthy volunteers received a single dose
labyrinth adverse events. In many cases, medical fol ow-up information
of warfarin 25 mg after taking tadalafil 10 mg or placebo once daily for 6
was limited. It is not possible to determine whether these reported events
days. Tadalafil reduced the exposure (AUC) to R- and S-warfarin by 11% and 13%, respectively but did not alter the ef ect of warfarin on prothrombin time
are related directly to the use of tadalafil, to the patient's underlying risk
(PT). The clinical implications of these findings are unclear. The possibility
factors for hearing loss, a combination of these factors, or to other factors.
of an increase or decrease in PT and/or international normalised ratio (INR)
should be considered when patients begin taking or cease taking tadalafil.
Table 3: Adverse events reported by patients treated with Tadalafil 2.5-
Ethinylestradiol – Tadalafil has been demonstrated to produce an increase
5 mg and more frequent on drug than placebo in phase 3 studies
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.
Theophylline – Tadalafil (10 mg) had no clinically significant effect on the
pharmacokinetics or pharmacodynamics of theophylline (CYP1A2 substrate).
The only pharmadynamic effect was a small (3.5 bpm) increase in heart rate.
Ef ects on Ability to Drive and Operate Machinery
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 tadalafil before driving or operating machinery.
A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with tadalafil once a day as compared
Ef ects on Laboratory Tests
with placebo. Most of these ECG abnormalities were not associated with
There are no data available that shows that tadalafil has an ef ect on
Adverse events identified from spontaneous post marketing surveil ance
CIALIS tablets contain lactose.
Adverse events identified from clinical trials
Uncommon; hypersensitivity reactions including rash and urticaria
Rare; facial oedema
Frequency not known; Stevens-Johnson syndrome and exfoliative dermatitis
own optimal window of responsiveness.
Patients with renal impairment
Uncommon; palpitations, tachycardia, chest pain
The recommended dose of CIALIS is 10 mg taken prior to anticipated
Rare; myocardial infarction
sexual activity and without regard to food for patients with mild or moderate
Frequency not known; unstable angina pectoris, ventricular arrhythmia,
renal impairment. Based on efficacy and tolerability the dose may be
sudden cardiac death
increased up to 20 mg. For patients with severe renal impairment 10 mg is
(b) Most of the patients in whom these events have been reported had
the maximum recommended dose.
pre-existing cardiovascular risk factors. However, it is not possible to
Patients with hepatic impairment
determine whether these events are related directly to these factors, to
The recommended dose of CIALIS is 10 mg taken prior to anticipated
tadalafil, to sexual activity, or to a combination of these or other factors.
sexual activity with or without food for patients with mild to moderate hepatic
impairment (Child-Pugh Class A or B). There are no available data about the
Uncommon; hypotension (more commonly reported when tadalafil is given to
administration of doses higher than 10 mg of tadalafil to patients with hepatic
patients who are already taking antihypertensive agents), hypertension
impairment. 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. (Refer
Common; abdominal pain
to Pharmacokinetics in Special Populations – Hepatic Impairment)
Uncommon; gastroesophageal reflux
Skin and subcutaneous tissue
In responder patients to on-demand regimen who anticipate a frequent use
Uncommon; hyperhidrosis (sweating)
of Cialis (i.e. at least twice weekly), a once daily regimen with the lowest dose
of CIALIS might be considered suitable, based on patient choice and the
Uncommon; blurred vision
Rare; visual field defect
In these patients the recommended dose is 5mg taken once a day at
Frequency not known: non-arteritic anterior ischemic optic neuropathy
approximately the same time of day. The dose must not exceed 5mg daily.
(NAION), retinal vascular occlusion.
The dose may be decreased to 2.5mg once a day based on individual
Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of
decreased vision including permanent loss of vision, has been reported rarely
There is insufficient evidence on the maximum duration of treatment. The
postmarketing in temporal association with the use of phosphodiesterase
appropriateness of continued use of the once-a-day regimen should be
type 5 (PDE5) inhibitors, including CIALIS. Most, but not al , of these patients
reassessed periodical y.
had underlying anatomic or vascular risk factors for development of NAION,
Patients with renal impairment
including but not necessarily limited to: low cup to disc ratio ("crowded disc"), Dosage adjustments are not required in patients with mild or moderate renal
age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia,
impairment. Once-a-day dosing of tadalafil is not recommended in patients
and smoking. It is not possible to determine whether these events are related
with severe renal impairment.
directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other
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 (Refer to
Rare; prolonged erections
Pharmacokinetics in Special Populations – Hepatic Impairment).
Frequency not known; priapism, spontaneous penile erection
Patients with Diabetes
Dosage adjustments are not required in patients with diabetes.
Very common; headacheCommon; dizziness
Rare; stroke(b), migraine, syncope, transient ischemic attacks(b)
Dosage adjustments are not required in elderly patients.
Frequency not known; seizures
(b) Most of the patients in whom these events have been reported had
Tadalafil has not been studied in subjects under 18 years of age.
pre-existing cardiovascular risk factors. However, it is not possible to
CIALIS can be taken with or without food.
determine whether these events are related directly to these factors, to
tadalafil, to sexual activity, or to a combination of these or other factors.
Single doses of up to 500 mg of tadalafil have been given to healthy subjects
and multiple daily doses of up to 100 mg have been given to patients.
Adverse events were similar to those seen at lower doses. In cases of
Ear and labyrinth disorders
overdose, standard supportive measures should be adopted as required.
Very rare; sudden decrease or loss of hearing(a)
Haemodialysis contributes negligibly to tadalafil elimination. In case of overdose, immediately contact the Poisons Information Centre (in Australia,
(a) Sudden decrease or loss of hearing has been reported in a small
number of postmarketing and clinical trial cases with the use of al PDE5
cal 13 11 26; in New Zealand cal 0800 764 766) for advice.
inhibitors, including tadalafil. In some of the cases, medical conditions
PRESENTATION AND STORAGE CONDITIONS
and other factors were reported that may have also played a role in the
CIALIS 20 mg tablets are presented in blister packs of 2*, 4 and 8 tablets per
ear and labyrinth adverse events. In many cases, medical fol ow-up
information was limited. It is not possible to determine whether these
CIALIS 10 mg tablets are presented in blister packs of 2*, 4 and 8* tablets
reported events are related directly to the use of tadalafil, to the patient's
underlying risk factors for hearing loss, a combination of these factors,
CIALIS 5 mg tablets are presented in blister packs of 28 tablets per carton
or to other factors.
*CIALIS 2.5mg are presented in blister packs of 28 tablets per carton.
DOSAGE AND ADMINISTRATION
*not currently available
Store below 25°C. Store in the original package.
The recommended dose of CIALIS is either 10 mg or 20 mg, taken prior to
NAME AND ADDRESS OF SPONSOR
anticipated sexual activity. The maximum recommended dose is 20 mg. The
Eli Lil y Australia Pty. Limited 112 Wharf Road, West Ryde NSW 2114
maximum recommended dosing frequency is once per day. CIALIS 10 and
POISON SCHEDULE OF THE MEDICINE
20 mg is intended for use prior to anticipated sexual activity and is not for continuous daily use.
CIALIS has been proven ef ective up to 36 hours after dosing and, in some
DATE OF APPROVAL
patients, as early as 16 minutes after dosing. Patients may initiate sexual
TGA Approval: 18 January 2008
activity at varying time points relative to dosing in order to determine their
Date of Most Recent Amendment: 24 September 2009
AUCLS00187 02/11 S&H LILCI0030
UNIVERSIDAD NACIONAL EXPERIMENTAL DE GUAYANA ESPECIALIZACIÓN EN SALUD OCUPACIONAL MENCIÓN MEDICINA DEL TRABAJO PREVALENCIA DE DISFUNCIÓN ERÉCTIL EN TRABAJADORES DE TALADROS PETROLEROS ANACO EDO. ANZOATEGUI Trabajo Especial de Grado para optar a la Especialización en Salud Ocupacional mención Medicina del Trabajo. Autor: Sheila P. Blasco Aguilera Tutor: Dra. YoilrmaVaccaro Campos
Ayuntamiento de Málaga Área de Igualdad de Oportunidades de la Mujer de investigación Málaga mujer "Situación de la Mujer Malagueña con Diversidad Funcional en el mercado laboral, así como lo relativo a la conciliación de la vida laboral, personal y familiar." Investigadora: Alejandra I. Rosset.