Zenavil

Tadalafil.

The 20mg tablets are yellow, round, convex film coated tablets with diameter of nucleus 10.3mm.
Each 20mg film-coated tablet contains 20mg tadalafil.
Excipient with known effect: lactose.
Each 20 mg film-coated tablet contains 245.5mg of lactose monohydrate.
Excipients/Inactive Ingredients: Tablet Core: Lactose monohydrate, Hydroxypropylcellulose, Croscarmellose sodium, Sodium laurilsulphate, Cellulose microcrystalline, Magnesium stearate.
Film coating: Hypromellose, Lactose monohydrate, Triacetin, Titanium dioxide (E171), Talc, Iron oxide yellow (E172).

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction. ATC code: G04BE08.
Pharmacology: Pharmacodynamics: Mechanism of action: Tadalafil is a selective, inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP).
Erectile dysfunction and benign prostatic hyperplasia: 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.
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.
Pharmacodynamic effects: Studies in vitro have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum and pancreas. The effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. Tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, and PDE4, enzymes which are found in the heart, brain, blood vessels, liver, and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also >10,000-fold more potent for PDE5 than for PDE7 through PDE10.
Clinical efficacy and safety: 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 mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mmHg, respectively) and no significant change in heart rate.
In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. Across all clinical studies, reports of changes in colour vision were rare (<0.1%).
Three studies were conducted in men to assess the potential effect on spermatogenesis of Tadalafil 10mg (one 6-month study) and 20mg (one 6-month and one 9-month study) administered daily. In two of these studies decreases were observed in sperm count and concentration related to tadalafil treatment of unlikely clinical relevance. These effects were not associated with changes in other parameters such as motility, morphology and FSH.
Erectile Dysfunction: For Tadalafil on-demand, three clinical studies were conducted in 1,054 patients in an at-home setting to define the period of responsiveness. Tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.
In a 12-week study performed in 186 patients (142 tadalafil, 44 placebo) with ED 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 10mg or 20mg (flexible-dose, on-demand) of 48% as compared to 17% with placebo.
For once-a-day evaluation of tadalafil at doses of 2.5mg, 5mg and 10mg, three clinical studies were initially conducted involving 853 patients of various ages (range 21-82 years) and ethnicities, with ED of various severities (mild, moderate, severe) and etiologies. In the two primary efficacy studies of general populations, the mean per-subject proportion of successful intercourse attempts were 57 and 67% on Tadalafil 5mg, 50% on Tadalafil 2.5mg as compared to 31 and 37% with placebo. In the study in patients with ED secondary to diabetes, the mean per-subject proportion of successful attempts were 41 and 46% on Tadalafil 5mg and 2.5mg, respectively, as compared to 28% with placebo. Most patients in these three studies were responders to previous on-demand treatment with PDE5 inhibitors. In a subsequent study, 217 patients who were treatment-naïve to PDE5 inhibitors were randomised to Tadalafil 5mg once a day vs placebo. The mean per-subject proportion of successful sexual intercourse attempts was 68% for Tadalafil patients compared to 52% for patients on placebo.
Tadalafil at doses of 2mg to 100mg has been evaluated in 16 clinical studies involving 3,250 patients, including patients with ED of various severities (mild, moderate, severe), etiologies, ages (range 21-86 years) and ethnicities. Most patients reported ED 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 ED 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.
Benign Prostatic Hyperplasia: Tadalafil was studied in 5 clinical studies (LVHG, LVHJ, LVHR, LVID of 12 weeks duration and LVIW of 26 weeks duration).
Study LVHG randomised 1,058 patients to receive either Tadalafil 2.5mg, 5mg, 10mg or 20mg for once daily use or placebo. Study LVHJ randomised 325 patients to receive either Tadalafil 5mg for once daily use or placebo. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension and other cardiovascular disease were included.
In each of these trials (LVHG and LVHJ), Tadalafil 5mg for once daily use resulted in statistically significant improvement in the total International Prostate Symptom Score (IPSS) compared to placebo. Mean total IPSS showed a decrease starting at the first scheduled observation (4 weeks) in Study LVHJ and remained decreased through 12 weeks. In the long-term open-label extension phase of the controlled study LVHG, in which patients received Tadalafil 5mg 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.
In Study LVHR, Tadalafil for once daily use was also shown to be effective in treating ED and the symptoms of BPH 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 daily use in this population. In this ED and BPH study, Tadalafil 5mg demonstrated statistical superiority over placebo for total IPSS and for the International Index of Erectile Function Erectile Function (IIEF EF) domain score (mean treatment difference, 4.7; p<0.001). The mean per-subject proportion of successful sexual intercourse attempts in this study was 71.9% for Tadalafil 5mg patients compared to 48.3% patients on placebo.
Study LVID randomised 511 patients to receive either Tadalafil 5mg, tamsulosin 0.4mg or placebo. Tadalafil 5mg resulted in statistically significant improvement in total IPSS. The efficacy of Tadalafil 5mg in treating BPH was observed as early as 1 week of therapy and was maintained through 12 weeks. Tadalafil 5mg for once daily use also improved measures of ED after 12 weeks of treatment compared with placebo in sexually active subjects with ED in the Primary Analysis Population, as demonstrated by statistically significant improvements in IIEF EF domain score (mean difference of the change, 4.0; p<0.001).
Data for Study LVHG, LVHJ, LVHR and LVID are shown as follows. (See Table 1.)

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In Study LVIW, Tadalafil for once daily use initiated together with finasteride was shown to be effective in treating the signs and symptoms of BPH in men with an enlarged prostate (>30cc) for up to 26 weeks. This double-blinded, parallel-design study of 26 weeks duration randomised 696 men to initiate either Tadalafil 5mg with finasteride 5mg or placebo with finasteride 5mg. The study population had a mean age of 64 years (range 46-86). Patients with multiple co-morbid conditions such as ED, diabetes mellitus, hypertension and other cardiovascular disease were included. Tadalafil with finasteride demonstrated statistically significant improvement in the signs and symptoms of BPH compared to placebo with finasteride, as measured by the total IPSS at 12 weeks, the primary study endpoint (see table 2 as follows). Key secondary endpoints demonstrated improvement in total IPSS starting at the first scheduled observation at Week 4 (Tadalafil -4.0, placebo -2.3; p<0.001) and the score remained decreased through 26 weeks (Tadalafil -5.5, placebo -4.5; p=0.022). However, the magnitude of the treatment difference between placebo/finasteride and Tadalafil/finasteride decreased from 1.7 points at Week 4 to 1.0 point at Week 26, as shown in the table and figure below. The incremental benefit of Tadalafil beyond 26 weeks is unknown. (See Table 2 and figure.)

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Click on icon to see table/diagram/image

In the 404 patients who had both ED and BPH at baseline, changes in erectile function were assessed as key secondary endpoints using the EF domain of the IIEF questionnaire. Tadalafil with finasteride (n=203) was compared to placebo with finasteride (n=201). A statistically significant improvement from baseline (Tadalafil/finasteride 13.7, placebo/finasteride 15.1) was observed at Week 4 (Tadalafil/finasteride 3.7, placebo/finasteride -1.1; p<0.001), Week 12 (Tadalafil/finasteride 4.7, placebo/finasteride 0.6; p<0.001) and Week 26 (Tadalafil/finasteride 4.7, placebo/finasteride 0.0; p<0.001).
Pharmacokinetics: Absorption: Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median time of 2 hours after dosing. Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food, thus it 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 litres at steady state, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Biotransformation: Tadalafil is predominantly metabolised by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.
Elimination: The mean oral clearance for tadalafil is 2.5 l/h at steady state and the mean half-life is 16 hours in healthy subjects.
Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Linearity/non-linearity: Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5mg to 20mg, 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 ED are similar to pharmacokinetics in subjects without ED.
Elderly: Healthy elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) relative to healthy subjects aged 19 to 45 years. This effect of age is not clinically significant and does not warrant a dose adjustment.
Renal Insufficiency: In clinical pharmacology studies using single dose tadalafil (5mg-20mg), tadalafil exposure (AUC) approximately doubled in subjects with mild (creatinine clearance 51 to 80ml/min) or moderate (creatinine clearance 31 to 50ml/min) renal impairment and in subjects with end-stage renal disease on dialysis. In haemodialysis patients, Cmax was 41% higher than that observed in healthy subjects. Haemodialysis contributes negligibly to tadalafil elimination. Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil is not recommended in patients with severe renal impairment.
Hepatic Insufficiency: Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh class A and B) is comparable to exposure in healthy subjects when a dose of 10mg is administered.
There is limited clinical data on the safety of tadalafil in patients with severe hepatic insufficiency (Child-Pugh class C). If Zenavil 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 10mg of tadalafil to patients with hepatic impairment. There are no available data about the administration of once-a-day dosing of tadalafil to patients with hepatic impairment. If Zenavil 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: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.
There was no evidence of teratogenicity, embryotoxicity, or foetotoxicity in rats or mice that received up to 1000mg/kg/day tadalafil. In a rat prenatal and postnatal development study, the no observed effect dose was 30mg/kg/day. In the pregnant rat the AUC for calculated free drug at this dose was approximately 18-times the human AUC at a 20mg dose.
There was no impairment of fertility in male and female rats. In dogs given tadalafil daily for 6 to 12 months at doses of 25mg/kg/day (resulting in at least a 3-fold greater exposure [range 3.7-18.6] than seen in humans given a single 20mg dose) and above, there was regression of the seminiferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs. See also Pharmacology: Pharmacodynamics as previously mentioned.

Zenavil is indicated for: Treatment of erectile dysfunction in adult males. In order for tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is required.
Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.
Zenavil is not indicated for women.

Posology: Erectile Dysfunction: Zenavil for Use as Needed: The recommended dose is 10mg taken prior to anticipated sexual activity. In those patients in whom tadalafil 10mg does not produce an adequate effect, the maximum dose is 20mg and the maximum dosing frequency is once per day. It may be taken from 30 minutes to 36 hours prior to sexual activity. Tadalafil 10mg and 20mg is intended for use prior to anticipated sexual activity and it is not recommended for continuous daily use.
Zenavil for Once Daily Use: In patients who anticipate a frequent use of Zenavil (i.e. at least twice weekly) a once daily regimen with the lowest doses of Zenavil might be considered suitable, based on patient choice and the physician's judgement. In these patients the recommended starting dose is 2.5mg once a day, taken at approximately the same time every day, without regard to timing of sexual activity. The dose may be increased to 5mg once a day, based on individual efficacy and tolerability. The appropriateness of continued use of the daily regimen should be reassessed periodically.
Benign Prostatic Hyperplasia: The recommended dose is 5mg, taken at approximately the same time every day. When therapy for BPH is initiated with Zenavil and finasteride, the recommended dose of Zenavil is 5mg, taken at approximately the same time every day for up to 26 weeks.
Erectile Dysfunction and Benign Prostatic Hyperplasia: The recommended dose is 5mg, taken at approximately the same time every day, without regard to timing of sexual activity.
Special populations: Elderly men: Dose adjustments are not required in elderly patients.
Men with renal impairment: Zenavil for Use as Needed: Mild (creatinine clearance 51 to 80 ml/min): No dose adjustment is required.
Moderate (creatinine clearance 31 to 50 ml/min): A starting dose of 5mg not more than once per day is recommended and the maximum dose is 10mg not more than once in every 48 hours.
Severe (creatinine clearance <30 ml/min or on hemodialysis): The maximum dose is 5mg not more than once in every 72 hours (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Zenavil for Once Daily Use: Mild (creatinine clearance 51 to 80 ml/min): No dose adjustment is required.
Moderate (creatinine clearance 31 to 50 ml/min): No dose adjustment is required.
Severe (creatinine clearance <30 ml/min or on hemodialysis): Zenavil for once daily use is not recommended (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Men with hepatic impairment: Zenavil for Use as Needed: The recommended dose is 10mg taken prior to anticipated sexual activity. There is limited clinical data on the safety of Zenavil in patients with severe hepatic impairment (Child-Pugh Class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10mg of tadalafil to patients with hepatic impairment.
Zenavil for Once Daily Use: Once-a-day dosing has not been extensively evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Men with diabetes: Dose adjustments are not required in diabetic patients.
Patients taking CYP3A4 Inhibitors: Zenavil for Use as Needed: For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of Zenavil is 10mg, not to exceed once every 72 hours (see Precautions and Interactions).
Zenavil for Once Daily Use: For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of Zenavil is 2.5mg (see Precautions and Interactions).
Method of administration: For oral use. Zenavil can be taken with or without food.

Single doses of up to 500mg have been given to healthy subjects, and multiple daily doses up to 100mg 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 the active substance or to any of the excipients listed in Description.
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.)
Tadalafil must not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.
The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated: Patients with myocardial infarction within the last 90 days.
Patients with unstable angina or angina occurring during sexual intercourse.
Patients with New York Heart Association class 2 or greater heart failure in the last 6 months.
Patients with uncontrolled arrhythmias, hypotension (<90/50mmHg), or uncontrolled hypertension.
Patients with a stroke within the last 6 months.
Tadalafil is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure (see Precautions).

Before treatment with tadalafil: A medical history and physical examination should be undertaken to diagnose erectile dysfunction or benign prostatic hyperplasia 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 potentiates the hypotensive effect of nitrates (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 and carefully assessed for cardiovascular conditions (see Contraindications).
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.
Cardiovascular: Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina pectoris, ventricular arrhythmia, stroke, transient ischaemic attacks, chest pain, palpitations and tachycardia, have been reported either post marketing and/or in clinical trials. Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to definitively determine whether these events are related directly to these risk factors, to tadalafil, to sexual activity, or to a combination of these or other factors.
In patients who are taking alpha1blockers, concomitant administration of tadalafil may lead to symptomatic hypotension in some patients (see Interactions). The combination of tadalafil and doxazosin is not recommended.
Tadalafil (5mg) - In patients receiving concomitant antihypertensive medicinal products, 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.
Vision: Visual defects and cases of NAION 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, he should stop taking tadalafil and consult a physician immediately (see Contraindications). Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical studies, and use in these patients is not recommended.
Renal and hepatic impairment: 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 clinical data on the safety of single-dose administration of tadalafil as treatment of erectile dysfunction or benign prostatic hyperplasia in patients with severe hepatic insufficiency (Child-Pugh class C). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.
Priapism and anatomical deformation of the penis: Priapism has been reported in men treated with PDE5 inhibitors. Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
Tadalafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia).
Use with CYP3A4 inducers or inhibitorsCaution 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 medicinal products are combined (see Interactions).
Tadalafil and other treatments for erectile dysfunctionThe safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. The patients should be informed not to take tadalafil in such combinations.
Zenavil contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: Tadalafil has negligible influence on the ability to drive or use machines. 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 using machines.

Pregnancy: Zenavil is not indicated for use by 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).
Fertility: Effects were seen in dogs that might indicate impairment of fertility. Two subsequent clinical studies suggest that this effect is unlikely in humans, although a decrease in sperm concentration was seen in some men (see Pharmacology: Pharmacodynamics and Pharmacology: Toxicology: Preclinical safety data under Actions).

The most commonly reported adverse reactions in patients taking Tadalafil for the treatment of ED or BPH 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. The majority of headaches reported with Tadalafil once-a-day dosing are experienced within the first 10 to 30 days of starting treatment.
The table as follows lists the adverse reactions observed from spontaneous reporting and in placebo-controlled clinical trials (comprising a total of 8,022 patients on Tadalafil and 4,422 patients on placebo) for on-demand and once-a-day treatment of ED and the once-a-day treatment of BPH.
Frequency convention: 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 (cannot be estimated from the available data). (See Table 3.)

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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.
Other special populations: Data in patients over 65 years of age receiving tadalafil in clinical trials, either for the treatment of ED or BPH, are limited. In clinical trials with tadalafil taken on-demand for the treatment of ED, diarrhoea was reported more frequently in patients over 65 years of age. In clinical trials with tadalafil 5mg taken once a day for the treatment of BPH, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.

Interaction studies were conducted with 10mg and/or 20mg tadalafil, as indicated below. With regard to those interaction studies where only the 10mg tadalafil dose was used, clinically relevant interactions at higher doses cannot be completely ruled out.
Effects of Other Substances on tadalafil: Cytochrome P450 inhibitors: Tadalafil is principally metabolised by CYP3A4.
A selective inhibitor of CYP3A4, ketoconazole (200mg daily), increased tadalafil (10mg) exposure (AUC) 2-fold and Cmax by 15%, relative to the AUC and Cmax values for tadalafil alone.
Ketoconazole (400mg daily) increased tadalafil (20mg) exposure (AUC) 4-fold and Cmax by 22%.
Ritonavir, a protease inhibitor (200mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20mg) exposure (AUC) 124% with no change in Cmax. Ritonavir (500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32% and decreased Cmax by 30%.
Although specific interactions have not been studied, other protease inhibitors, such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole, and grapefruit juice, should be co-administered with caution, as they would be expected to increase plasma concentrations of tadalafil (see Precautions). Consequently, the incidence of the adverse reactions listed in Adverse Reactions might be increased.
Transporters: The role of transporters (for example, p-glycoprotein) in the disposition of tadalafil is not known. Therefore, there is the potential of drug interactions mediated by inhibition of transporters.
Cytochrome P450 inducers: A CYP3A4 inducer, rifampicin (600 mg daily), reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone (10mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil; the magnitude of decreased efficacy is unknown.
Other inducers of CYP3A4, such as phenobarbital, phenytoin, and carbamazepine, may also decrease plasma concentrations of tadalafil.
Effects of tadalafil on Other Medicinal Products: Nitrates: In clinical studies, tadalafil (5mg, 10mg and 20mg) 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 received daily doses of tadalafil 20mg for 7 days and 0.4mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last tadalafil dose. Thus, in a patient prescribed any dose of tadalafil (5mg-20mg), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours 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.
Anti-hypertensives (including calcium channel blockers): The co-administration of doxazosin (4 and 8mg daily) and tadalafil (5mg daily dose and 20mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore, this combination is not recommended (see 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.
In clinical pharmacology studies, the potential for tadalafil to augment the hypotensive effects of antihypertensive medicinal products was examined. Major classes of antihypertensive medicinal products were studied, either as monotherapy or as part of combination therapy, including calcium-channel blockers (amlodipine), angiotensin converting enzyme (ACE) inhibitors (enalapril), beta-adrenergic receptor blockers (metoprolol), thiazide diuretics (bendrofluazide), and angiotensin II receptor blockers (various types and doses, alone or in combination with thiazides, calcium-channel blockers, beta-blockers, and/or alpha-blockers). Tadalafil (10mg, except for studies with angiotensin II receptor blockers and amlodipine in which a 20mg dose was applied) had no clinically significant interaction with any of these classes. In another clinical pharmacology study, tadalafil (20mg) 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 medicinal products, tadalafil 20mg may induce a blood pressure decrease, which (with the exception of alpha-blockers - see as previously mentioned) is, in general, minor and not likely to be clinically relevant.
Analysis of Phase 3 clinical trial data showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medicinal products. However, appropriate clinical advice should be given to patients regarding a possible decrease in blood pressure when they are treated with antihypertensive medicinal products.
Riociguat: Preclinical studies showed an additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated (see Contraindications).
5-alpha reductase inhibitors: In a clinical trial that compared tadalafil 5 mg coadministered with finasteride 5 mg to placebo plus finasteride 5 mg in the relief of BPH symptoms, no new adverse reactions were identified. However, as a formal drug-drug interaction study evaluating the effects of tadalafil and 5-alpha reductase inhibitors (5-ARIs) has not been performed, caution should be exercised when tadalafil is co-administered with 5-ARIs.
CYP1A2 substrates (e.g. theophylline): When tadalafil 10mg was administered with theophylline (a non-selective phosphodiesterase inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction. The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate. Although this effect is minor and was of no clinical significance in this study, it should be considered when co-administering these medicinal products.
Ethinylestradiol and terbutaline: Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinylestradiol; a similar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.
Alcohol: Alcohol concentrations (mean maximum blood concentration 0.08%) were not affected by co-administration with tadalafil (10mg or 20mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximise the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol). Tadalafil (20mg) did not augment the mean blood pressure decrease produced by alcohol (0.7g/kg or approximately 180ml 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 (0.6g/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 (10mg).
Cytochrome P450 metabolised medicinal products: 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.
CYP2C9 substrates (e.g. R-warfarin): Tadalafil (10mg and 20mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.
Aspirin: Tadalafil (10mg and 20mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.
Antidiabetic medicinal products: Specific interaction studies with antidiabetic medicinal products were not conducted.
Digoxin: Co-administration of tadalafil 40mg once per day for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin 0.25 mg/day in healthy subjects.

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: No special requirements.

Shelf life: 36 months.
Store below 30°C in the original package.

Drugs for Erectile Dysfunction & Ejaculatory Disorders

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

POM