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NAME
CIALIS® (tadalafil).
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: DESCRIPTION
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,
Cialis Approved
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
Pharmacodynamics
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.
improved erections.
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[1] 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.
antihypertensive therapy.
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[1]-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 Tadalafil Placebo 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 Respiratory System 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 Cardiovascular System 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 hyperaemia; sensations 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) Once-a-day Dosing 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). Respiratory System The only pharmadynamic effect was a small (3.5 bpm) increase in heart rate.
Digestive System Musculoskeletal System Ef ects on Ability to Drive and Operate Machinery Although the frequency of reports of dizziness in placebo and tadalafil arms Cardiovascular System 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 reactions.
laboratory tests.
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.
Cardiac Disorders(b) 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 Vascular Disorders 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 Once-a-Day Dosing: 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 Urogenital System 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 Respiratory System and multiple daily doses of up to 100 mg have been given to patients. Uncommon; epistaxis 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 On-Demand Dosing: 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

Source: http://researchreview.com.au/Cialis_PI.pdf

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