Cialis

Tadalafil.

Each tablet contains tadalafil 5 mg and 20 mg.
Excipients/Inactive Ingredients: Tablet Core: Lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, sodium laurylsulfate and magnesium stearate. Film-Coat: Lactose monohydrate [127 mg (for Cialis 5 mg only)], hypromellose, triacetin, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172) (for Cialis 5 mg only) and talc.

Pharmacotherapeutic Group: Drugs used in erectile dysfunction. ATC Code: G04B E. Cialis 5 mg: G04B E08.
Pharmacology: Pharmacodynamics: Mechanism of Action: Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the treatment of erectile dysfunction in the absence of sexual stimulation.
Cialis 5 mg: The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.
Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung and cerebellum. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2 and PDE4, and PDE7 (for Cialis 20 mg only) enzymes which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscles and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also >10,000-fold more potent for PDE5 than for PDE7 through PDE10.
Cialis 20 mg: Tadalafil is also >9,000 - fold more potent for PDE5 than for PDE 8, 9, and 10 and 14 - fold more potent for PDE5 than for PDE 11. The tissue distribution and physiological effects of the inhibition of PDE8 through PDE11 have not been elucidated.
Clinical Efficacy and Safety: Cialis 5 mg: TADALAFIL administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mm Hg, respectively), and no significant change in heart rate.
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of changes in colour vision were rare (<0.1%).
Studies on Spermatogenesis: Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the 3 studies. In the study of tadalafil 10 mg for 6 months and the study of tadalafil 20 mg for 9 months, results showed a decrease in mean sperm concentrations relative to placebo. This effect was not seen in the study of tadalafil 20 mg taken for 6 months. In the 9-month study, decreases in sperm concentration were associated with higher ejaculatory frequency. Ejaculation frequency was not assessed in the 6-month studies. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle-stimulating hormone (FSH) with either 10 or 20 mg of tadalafil compared to placebo.
Erectile Dysfunction: Three clinical studies were conducted in 1,054 patients in an at-home setting to define the period of responsiveness to Tadalafil. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hrs following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.
Cialis 5 mg: In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-dose, on demand) of 48% as compared to 17% with placebo.
Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3,250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years), and ethnicities. Most patients reported erectile dysfunction of at least 1 year in duration. In the primary efficacy studies of general populations, 81% of patients reported that TADALAFIL improved their erections as compared to 35% with placebo.
Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking TADALAFIL (86%, 83%, and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with placebo).
In the primary efficacy studies, 75% of intercourse attempts were successful in TADALAFIL treated patients as compared to 32% with placebo.
For once-a-day evaluation of tadalafil at doses of 2.5, 5, and 10 mg, 3 clinical studies were initially conducted involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile dysfunction of various severities (mild, moderate, severe), etiologies. Most patients in all three studies were responders to previous on-demand treatment with PDE5 inhibitors. In the two primary efficacy studies of general populations, the mean per-subject proportion of successful attempts were 57 and 67% on TADALAFIL 5 mg, 50% on TADALAFIL 2.5 mg as compared to 31 and 37% with placebo. In the study in patients with erectile dysfunction secondary to diabetes, the mean per-subject proportion of successful attempts were 41 and 46% on TADALAFIL 5 mg and 2.5 mg, respectively, as compared to 28% with placebo.
Benign prostatic hyperplasia: TADALAFIL was studied in men with signs and symptoms of benign prostatic hyperplasia in 4 randomized, multi-national, double-blind, placebo-controlled, parallel-design primary efficacy and safety studies of 12 weeks duration enrolling over 1,500 patients of various ages (range 45-92 years). In the integrated data from these 4 studies, TADALAFIL 5 mg (n=742; mean change fro m baseline of -5.0) demonstrated statistical superiority over placebo (n=735; mean change from baseline of -2.7) in improving the total International Prostate Symptom Score (IPSS; mean treatment difference for tadalafil compared to placebo of -2.3, p<.001) in the overall benign prostatic hyperplasia population. Similarly, in each of the individual studies, patients treated with TADALAFIL 5 mg had statistically significantly greater decrease in total IPSS as compared to placebo after 12 weeks of treatment. Data for each study are shown below. (See Table 1.)

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The improvement in total IPSS in the tadalafil group compared to placebo occurred as early as 1 week in the integrated data from Studies LVHJ and LVID (mean difference of -1.3, p<.001) and 2 weeks in Study LVHR (mean difference of -1.8, p<.001).
In the long-term open-label extension phase of the controlled study LVHG, in which patients received TADALAFIL 5 mg for up to 1 year after the 12-week double-blind treatment period, the improvement in total IPSS induced by tadalafil at week 12 of double-blind treatment was maintained over 1 year.
For the Benign prostatic hyperplasia Impact Index (BII), the key secondary efficacy measure, TADALAFIL 5 mg (n=735; mean change from baseline of -1.6) demonstrated statistical superiority over placebo (n=725; mean change from baseline of -0.9) in improving the BII (mean treatment difference for tadalafil compared to placebo of -0.7, p<.001) in the integrated data from the 4 studies.
TADALAFIL for once a day use was also shown to be effective in treating erectile dysfunction and the symptoms of benign prostatic hyperplasia in patients with both conditions based on results from one of the placebo-controlled, double-blind, parallel-arm efficacy and safety studies which specifically assessed the efficacy and safety of TADALAFIL for once a day use in this population (Study LVHR). In this erectile dysfunction and benign prostatic hyperplasia study, TADALAFIL 5 mg demonstrated statistical superiority over placebo for total IPSS (mean treatment difference, -2.3; p<.001) and for the International Index of Erectile Function Erectile Function (IIEF EF) domain score (mean treatment difference, 4.7; p<.001). The mean per-subject proportion of successful sexual intercourse attempts in this study was 71.9% for TADALAFIL 5 mg patients compared to 48.3% patients on placebo.
Cialis 20 mg: CIALIS (20 mg) administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mm Hg, respectively), in standing systolic and diastolic blood pressure compared to placebo (mean maximal decrease of 0.2/4.6 mm Hg, respectively), and no significant change in heart rate. Larger effects were recorded among subjects receiving concomitant nitrates.
In a study to assess the effects of tadalafil (40 mg) on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. In addition, no effects were observed on visual acuity, electroretinograms, intraocular pressure, or pupillometry. Across all clinical studies, reports of changes in colour vision were rare (<0.1 %).
Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3,250 patients, including patients with erectile dysfunction of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years), ethnicities and durations of ED. Most patients reported erectile dysfunction of at least 1 year in duration. In the primary efficacy studies of general populations, 81% of patients reported that CIALIS improved their erections as compared to 35% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections whilst taking CIALIS (86%, 83%, and 72% for mild, moderate, and severe, respectively, as compared to 45%, 42%, and 19% with placebo). In the primary efficacy studies, 75% of intercourse attempts were successful in CIALIS treated patients as compared to 32% with placebo.
In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with erectile dysfunction secondary to spinal cord injury, tadalafil significantly improved the erectile function leading to a mean per-subject proportion of successful attempts in patients treated with tadalafil 10 or 20 mg (flexible-dose, on demand) of 48% as compared to 17% with placebo.
Pharmacokinetics: Absorption: Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (C_max) is achieved at a median time of 2 hrs after dosing. Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food, thus tadalafil may be taken with or without food. The time of dosing (morning versus evening) had no clinically relevant effects on the rate and extent of absorption.
Distribution: The mean volume of distribution is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein-binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Biotransformation: Tadalafil is predominantly metabolised by the cytochrome P-450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
Elimination: The mean oral clearance for tadalafil is 2.5 L/hr and the mean half-life is 17.5 hrs in healthy subjects.
Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Linearity/Nonlinearity: Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5-20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once-daily dosing.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction.
Special Populations: Elderly: Healthy elderly subjects (≥65 years), had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.
Renal Insufficiency: In a clinical pharmacology studies using single-dose tadalafil (5-20 mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51-80 mL/min) or moderate (creatinine clearance 31-50 mL/min) renal impairment and in subjects with end-stage renal disease on dialysis. In haemodialysis patients, C_max was 41% higher than that observed in healthy subjects. Haemodialysis contributes negligibly to tadalafil elimination.
Hepatic Insufficiency: Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when a dose of 10 mg is administered. There is limited clinical data on the safety of tadalafil in patients with severe hepatic insufficiency (Child-Pugh class C); if tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of tadalafil to patients with hepatic impairment.
Cialis 5 mg: If Tadalafil is prescribed once-a-day, a careful individual benefit-risk evaluation should be undertaken by the prescribing physician.
Patients with Diabetes: Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.
Toxicology: Preclinical Safety Data: There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1,000 mg/kg/day tadalafil. In a rat pre- and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated-free drug at this dose was approximately 18 times the human AUC at a 20 mg dose.
Cialis 5 mg: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction.
Cialis 20 mg: Tadalafil was not carcinogenic to rats or mice when administered for 24 months.
Tadalafil was not mutagenic or genotoxic in in vitro bacterial and mammalian cell assays, and in vitro human lymphocytes and in vivo rat micronucleus assays.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6-12 months at doses of 25 mg/kg/day [resulting in at least a 3-fold greater exposure (range 3.7-18.6) than seen in humans given a single 20-mg dose] and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. (See also Pharmacodynamics as previously mentioned.)

Treatment of erectile dysfunction in adult males.
In order for tadalafil to be effective for the treatment of erectile dysfunctiom, sexual stimulation is required.
Cialis 5 mg: Treatment of signs and symptoms of benign prostatic hyperplasia in adult males including those with erectile dysfunction.
Tadalafil is not indicated for use by women.

For oral use.
Erectile dysfunction in adult men: In general, the recommended dose is 10 mg taken prior to anticipated sexual activity and with or without food. In those patients in whom tadalafil 10 mg does not produce an adequate effect, 20 mg might be tried. It may be taken at least 30 min prior to sexual activity.
The maximum dosing frequency is once daily.
Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and is not recommended for continuous daily use.
Cialis 5 mg: In responder patients to on-demand regimen who anticipate a frequent use of TADALAFIL (i.e., at least twice weekly) a once daily regimen with the lowest doses of TADALAFIL might be considered suitable, based on patient choice and the physician's judgment.
Cialis 20 mg: Continuous daily use of the medication is strongly discouraged because the long term safety after prolonged daily dosing has not been established and also because the effect of tadalafil usually lasts for longer than one day. (See Precautions and Pharmacology: Pharmacodynamics under Actions.)
Cialis 5 mg: Benign prostatic hyperplasia in adult men: The recommended dose is 5 mg taken at approximately the same time every day with or without food. For adult men being treated for both being treated for both benign prostatic hyperplasia and erectile dysfunction, the recommended dose is also 5 mg taken at approximately the same time every day.
Use in elderly men: Dosage adjustments are not required in elderly patients.
Use in men with impaired renal function: Dosage adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment, 10 mg is the maximum recommended dose for on-demand treatment.
Cialis 5 mg: Once-a-day dosing of 2.5 or 5 mg TADALAFIL both for the treatment of erectile dysfunction or benign prostatic hyperplasia is not recommended in patients with severe renal impairment. (See Precautions and Pharmacology: Pharmacokinetics under Actions.)
Use in men with impaired hepatic function: The recommended dose of Tadalafil is 10 mg taken prior to anticipated sexual activity and without regard to food. There is limited clinical data on the safety of tadalafil in patients with severe hepatic insufficiency (Child-Pugh class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses >10 mg of tadalafil to patients with hepatic impairment. (See Pharmacology: Pharmacokinetics under Actions and Precautions).
Cialis 5 mg: Once-a-day dosing of TADALAFIL both for the treatment of erectile dysfunction and benign prostatic hyperplasia has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. (See Pharmacology: Pharmacokinetics under Actions.)
Use in men with diabetes: Dosage adjustments are not required in diabetic patients.
Use in children and adolescents: Tadalafil should not be used in individuals <18 years.

Single doses of up to 500 mg have been given to healthy subjects and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses.
In cases of overdose, standard supportive measures should be adopted as required.
Haemodialysis contributes negligibly to tadalafil elimination.

Hypersensitivity to tadalafil or any of the excipients of Cialis.
In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see Interactions).
Agents for the treatment of erectile dysfunction, including tadalafil, should not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.
The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated: Patients with myocardial infarction within the last 90 days; with unstable angina or angina occurring during sexual intercourse; with New York Heart Association Class ≥2 heart failure in the last 6 months; with uncontrolled arrhythmias, hypotension (<90/50 mmHg) or uncontrolled hypertension; with a stroke within the last 6 months.
Cialis 5 mg: Tadalafil is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see Precautions).

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Tadalafil has vasodilator properties, resulting in mild and transient decreases in blood pressure (see Pharmacology: Pharmacodynamics under Actions) and as such potentiate the hypotensive effect of nitrates. Prior to prescribing tadalafil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects (see Contraindications).
Prior to initiating treatment with Tadalafil for benign prostatic hyperplasia patients should be examined to rule out the presence of carcinoma of the prostate.
In patients receiving concomitant antihypertensive medicines, tadalafil may induce a blood pressure decrease. When initiating daily treatment with tadalafil, appropriate clinical considerations should be given to a possible dose adjustment of the antihypertensive therapy.
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, palpitations and tachycardia have been reported either post-marketing and/or in clinical trials. In addition, hypertension and hypotension (including postural hypotension) were also seen infrequently in clinical trials. Most of the patients in whom these events have been reported had preexisting cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to tadalafil, to sexual activity, or to a combination of these or other factors.
Cialis 5 mg: Visual defects and cases of non-arteritic ischemic optic neuropathy have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, the patient should stop taking tadalafil and consult a physician immediately (see Contraindications).
Due to increased tadalafil exposure (AUC), limited clinical experience and the lack of ability to influence clearance by dialysis, once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment.
There is limited or no clinical data on the safety of single-dose administration of tadalafil in patients with severe hepatic insufficiency (Child-Pugh class C). Once-a-day administration has not been extensively evaluated in patients with hepatic insufficiency. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.
Cialis 20 mg: Nonarteritic anterior ischemic optic neuropathy (NAION) is a cause of decreased vision including permanent loss of vision. There are rare postmarketing reports of NAION in temporal association with the use of all PDE5 inhibitors. Currently it is not possible to determine whether NAION is related directly to the use of PDE5 inhibitors or other factors. Physicians should advise patients to stop use of tadalafil and seek immediate medical attention in the event of a sudden loss of vision. Physicians should also discuss with patients that individuals who have already experienced NAION are at increased risk of NAION.
The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors have not been studied. Therefore, the use of such combinations is not recommended.
There is no clinical data on the safety of CIALIS in patients with severe hepatic insufficiency (Child-Pugh Class C); it prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.
Patients who experience erections lasting 4 hrs or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
Agents for the treatment of erectile dysfunction, including tadalafil should be used with caution in patients with anatomical deformation of the penis (eg, angulation, cavernosal fibrosis or Peyronie's disease) or in patients who have conditions which may predispose them to priapism (eg, sickle cell anaemia, multiple myeloma or leukaemia).
The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment. It is not known if tadalafil is effective in patients who have undergone pelvic surgery or radical non-nerve-sparing prostatectomy.
In patients who are taking α₁-blockers eg, doxazosin, concomitant administration of tadalafil may lead to symptomatic hypotension in some patients (see Interactions). Therefore, the combination of tadalafil and α-blockers is not recommended.
The combination of tadalafil and guanylate cyclase stimulation is not recommended because it may lead to symptomatic hypotension.
Caution should be exercised when prescribing tadalafil to patients using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole and erythromycin) as increased tadalafil exposure (AUC) has been observed if the medicine are combined (see Interactions).
The safety and efficacy of combinations of tadalafil and other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
Tadalafil contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Cialis 20 mg: In dogs given tadalafil daily for 6 to 12 months at doses of 25 mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans at a 20 mg single dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. Results from two 6 month studies in volunteers suggest that this effect is unlikely in humans (see Pharmacology: Pharmacodynamic under Actions). The effects of longer term daily dosing have not been established. Therefore, daily use of the medication is strongly discouraged.
Effects on the Ability to Drive or Operate Machinery: No studies or no or negligible influence on the effect on the ability to drive and or use machines have been performed. Although the frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, patients should be aware of how they react to tadalafil before driving or operating machinery.

Tadalafil is not indicated for use by women.
Cialis 5 mg: There are limited data from the use of tadalafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions). As a precautionary measure, it is preferable to avoid the use of TADALAFIL during pregnancy.
Available pharmacodynamic/toxicological data in animals have shown excretion of tadalafil in milk. A risk to the suckling child cannot be excluded. TADALAFIL should not be used during breast feeding.
Cialis 20 mg: There are no studies of tadalafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions).
There was no evidence of teratogenicity, embryotoxicity or foetotoxicity in rats or mice that received up to 1000 mg/kg/day. In a rat pre- and postnatal development study, the no observed effect dose was 30 mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose is approximately 18 or 6 times the human AUC at a 20- or 40 mg dose, respectively.

Cialis 5 mg: Summary of the safety profile: The most commonly reported adverse reactions in patients taking TADALAFIL for the treatment of erectile function or benign prostatic hyperplasia were headache, dyspepsia, back pain and myalgia, in which the incidences increase with increasing dose of TADALAFIL.
The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age.
Tabulated summary of adverse reactions: The table below (table 2) lists the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 7,116 patients on TADALAFIL and 3,718 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the once-a-day treatment of benign prostatic hyperplasia.
Adverse reactions: Frequency estimate: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very Rare (<1/10,000) and Not known (events not reported in registration trials cannot be estimated postmarketing spontaneous reports). (See Table 2.)

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Description of selected adverse reactions: A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.
Cialis 20 mg: The most commonly reported adverse reactions were headache and dyspepsia. The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age.
The table below (table 3) lists the adverse reactions reported during placebo-controlled clinical trials for registration in patients treated with CIALIS. Adverse reactions are also included that have been reported from postmarketing surveillance.
Adverse reactions: Frequency estimate: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very Rare (<1/10,000) and Not known (events not reported in registration trials cannot be estimated from postmarketing spontaneous reports). (See Table 3.)

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Interaction studies were conducted with tadalafil 10 mg and/or 20 mg, as indicated as follows. With regard to those interaction studies where only the tadalafil 10-mg dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.
Effects of Other Medicinal Products on Tadalafil: Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (200 mg daily), increased tadalafil (10 mg) exposure (AUC) 2-fold and C_max by 15% relative to the AUC and C_max values for tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) exposure (AUC) 4-fold and C_max by 22%. Ritonavir, a protease inhibitor (200-mg dose given twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19 and CYP2D6, increased tadalafil (20 mg) exposure (AUC) 2-fold with no change in C_max. Although specific interactions have not been studied, other protease inhibitors eg, saquinavir and other CYP3A4 inhibitors eg, erythromycin, clarithromycin, itraconazole and grapefruit juice should be co-administered with caution as they would be expected to increase plasma concentrations of tadalafil (see Precautions). Consequently the incidence of the undesirable effects listed in Adverse Reactions might be increased.
The role of transporters (eg, p-glycoprotein) in the disposition of tadalafil is not known. There is, thus, the potential of drug interactions mediated by inhibition of transporters.
A selective CYP3A4 inducer, rifampicin 600 mg daily, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone (10-mg dose). This reduced exposure can be anticipated to decrease the efficacy of tadalafil; the magnitude of decreased efficacy is unknown. It can be expected that concomitant administration of other inducers of CYP3A4 eg, phenobarbital, phenytoin and carbamazepine may also decrease plasma concentrations of tadalafil.
Effects of Tadalafil on Other Medicinal Products: In clinical studies, tadalafil (5 mg and 20 mg) was shown to augment the hypotensive effects of nitrates. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated (see Contraindications). Based on the results of a clinical study in which 150 subjects receiving daily doses of tadalafil 20 mg for 7 days and sublingual nitroglycerin 0.4 mg at various times, this interaction lasted for >24 hrs and was no longer detectable when 48 hrs had elapsed after the last tadalafil dose. Thus, in a patient prescribed tadalafil (2.5-20 mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hrs should have elapsed after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.
Cialis 20 mg: Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does n ot inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19.
Tadalafil (20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.
Tadalafil (20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.
In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive agents was examined. Major classes of antihypertensive agents were studied, including calcium channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors (enalapril), β-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide) and angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides, calcium channel blockers, β-blockers, and/or α-blockers). Tadalafil (10 mg except for studies with angiotensin II receptor blockers and amlodipine in which a 20-mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study tadalafil (20 mg) was studied in combination with up to 4 classes of antihypertensives. In subjects taking multiple antihypertensives, the ambulatory-blood-pressure changes appeared to relate to the degree of blood-pressure control. In this regard, study subjects whose blood pressure was well controlled, the reduction was minimal and similar to that seen in healthy subjects. In study subjects whose blood pressure was not controlled, the reduction was greater although this reduction was not associated with hypotensive symptoms in the majority of subjects. In patients receiving concomitant antihypertensive medicines, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of α-blockers, see as follows) is, in general, minor and not like to be clinically relevant. Analysis of phase 3 clinical trial data showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medications. However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicines.
Cialis 5 mg: The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, incluing syncope. Therefore this combination is not recommended (see Precautions).
In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin. However, caution should be exercised when using tadalafil in patients treated with any alpha-blockers, and notably in the elderly. Treatments should be initiated at minimal dosage and progressively adjusted.
Cialis 20 mg: Alpha adrenergic-blockers: In two clinical pharmacology studies, no significant decreases in blood pressure were observed when tadalafil was co-administered to healthy subjects taking the selective alpha[1A]-adrenergic blocker, tamsulosin. When tadalafil was co-administered to healthy subjects taking doxazosin (4-8 mg daily), an alpha[1]-adrenergic blocker, there was an augmentation of the blood-pressure-lowering effect of doxazosin. The number of subjects with potentially clinically significant standing-blood-pressure decreases was greater for the combination. In these clinical pharmacology studies there were symptoms associated with the decrease in blood pressure including syncope.
Alcohol concentrations (mean maximum blood concentration 0.08 %) were not affected by co-administration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen 3 hrs after co-administration with alcohol. Alcohol was administered in a manner to maximize the rate of alcohol absorption (overnight fast with no food until 2 hrs after alcohol). Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol [0.7 g/kg or approximately 180 mL of 40% alcohol (vodka) in an 80-kg male] but in some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).
Tadalafil has been demonstrated to produce an increase in the oral bioavailabilty of ethinylestradiol; a similar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.
When tadalafil 10 mg was administered with theophylline (a nonselective phosphodiesterase inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor and was of no clinical significance in this study, it should be considered when co-administering these medications.
Cialis 5 mg: Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of medicinal products metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9 and CYP2C19.
Tadalafil (10 and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.
Tadalafil (10 and 20 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid.
Specific interaction studies with antidiabetic agents were not conducted.
Cialis 20 mg: H2 antagonists: An increase in gastric pH resulting from administration of nizatidine had no significant effect on tadalafil pharmacokinetics.
Antacids (magnesium hydroxide/aluminum hydroxide): Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.

Instruction for Use and Handling: No special requirements.
Incompatibilities: Not applicable.

Do not store above 30°C (below 25°C) in the original package. Protect from moisture.
Shelf-Life: 3 years.

Drugs for Bladder & Prostate Disorders / Drugs for Erectile Dysfunction & Ejaculatory Disorders

G04BE08 - tadalafil ; Belongs to the class of drugs used in erectile dysfunction.

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