Tadalafil

Bosentan (125 mg twice daily), a substrate of CYP2C9 and CYP3A4 and a moderate inducer of CYP3A4, CYP2C9 and possibly CYP2C19, reduced tadalafil (40 mg once per day) systemic exposure by 42% and C_max by 27% following multiple dose co-administration. The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated. Tadalafil did not affect the exposure (AUC and C_max) of bosentan or its metabolites. The safety and efficacy of combinations of tadalafil and other endothelin-1 receptor antagonists have not been studied.

Tadalafil (10 mg and 20 mg) had no clinically significant effect on exposure (AUC) to S-warfarin or R-warfarin (CYP2C9 substrate), nor did tadalafil affect changes in prothrombin time induced by warfarin.

A CYP3A4 inducer, rifampicin, reduced tadalafil AUC by 88%, relative to the AUC values for tadalafil alone (10 mg). This reduced exposure can be anticipated to decrease the efficacy of tadalafil; the magnitude of decreased efficacy is unknown. Other inducers of CYP3A4 such as phenobarbital, phenytoin and carbamazepine, may also decrease plasma concentrations of tadalafil.

For patients chronically taking potent inducers of CYP3A4, such as rifampicin, the use of tadalafil is not recommended.

Erectile dysfunction / benign prostatic hyperplasia

For the treatment of erectile dysfunction using on-demand tadalafil the recommended dose of tadalafil is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of tadalafil in patients with severe hepatic impairment (Child-Pugh Class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of tadalafil to patients with hepatic impairment.

Once-a-day dosing 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.

Pulmonary arterial hypertension (PAH), functional class II and III

Adults and paediatric population (2 to 17 years, weighing at least 40 kg)

Due to limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B), a starting dose of 20 mg once per day may be considered.

Paediatric population (2 to 17 years, weighing less than 40 kg)

In patients <40 kg and with mild to moderate hepatic impairment, a starting dose of 10 mg once per day may be considered.

For patients of all ages, if tadalafil is prescribed, a careful individual benefit/risk assessment should be undertaken by the prescribing physician. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of tadalafil is not recommended.

Alcohol concentrations (mean maximum blood concentration 0.08%) were not affected by coadministration with tadalafil (10 mg or 20 mg). In addition, no changes in tadalafil concentrations were seen 3 hours after co-administration with alcohol. Alcohol was administered in a manner to maximise the rate of alcohol absorption (overnight fast with no food until 2 hours after alcohol). Tadalafil (20 mg) did not augment the mean blood pressure decrease produced by alcohol (0.7 g/kg or approximately 180 ml of 40% alcohol [vodka] in an 80-kg male) but in some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone. The effect of alcohol on cognitive function was not augmented by tadalafil (10 mg).

For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the use of tadalafil is not recommended.

Adults and paediatric population (2 to 17 years, weighing at least 40 kg)

In patients with mild to moderate renal impairment a starting dose of 20 mg once per day is recommended. The dose may be increased to 40 mg once per day, based on individual efficacy and tolerability.

Paediatric population (2 to 17 years, weighing less than 40 kg)

In patients <40 kg and with mild to moderate renal impairment a starting dose of 10 mg once per day is recommended. The dose may be increased to 20 mg once per day, based on individual efficacy and tolerability.

Erectile dysfunction / benign prostatic hyperplasia

For patients with severe renal impairment 10 mg is the maximum recommended dose for on-demand treatment.

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.

Pulmonary arterial hypertension (PAH), functional class II and III

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.

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.

The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore, this combination is not recommended.

In interaction studies performed in a limited number of healthy volunteers, these effects were not reported with alfuzosin or tamsulosin.

In clinical pharmacology studies, the potential for tadalafil (10 and 20 mg) 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. In patients taking multiple antihypertensive medicinal products whose hypertension was not well controlled, greater reductions in blood pressure were observed compared to patients whose blood pressure was well controlled, where the reduction was minimal and similar to that in healthy subjects. In patients receiving concomitant antihypertensive medicinal products, tadalafil 20 mg may induce a blood pressure decrease, which (with the exception of doxazosin - see above) is, in general, minor and not likely to be clinically relevant.

Oral contraceptive

At steady-state, tadalafil (40 mg once per day) increased ethinylestradiol exposure (AUC) by 26% and C_max by 70% relative to oral contraceptive administered with placebo. There was no statistically significant effect of tadalafil on levonorgestrel which suggests the effect of ethinylestradiol is due to inhibition of intestinal sulphation by tadalafil. The clinical relevance of this finding is uncertain.

Terbutaline

A similar increase in AUC and C_max seen with ethinylestradiol may be expected with oral administration of terbutaline, probably due to inhibition of intestinal sulphation by tadalafil. The clinical relevance of this finding is uncertain.

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.

Ritonavir (200 mg twice daily), which is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) single dose exposure (AUC) 2-fold with no change in C_max. Ritonavir (500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32% and decreased C_max by 30%.

In patients who are taking alpha1 blockers, concomitant administration of tadalafil may lead to symptomatic hypotension in some patients.

The co-administration of doxazosin (4 and 8 mg daily) and tadalafil (5 mg daily dose and 20 mg as a single dose) increases the blood pressure-lowering effect of this alpha-blocker in a significant manner. This effect lasts at least twelve hours and may be symptomatic, including syncope. Therefore this combination is not recommended.

The efficacy and safety of tadalafil co-administered with prostacyclin or its analogues has not been studied in controlled clinical trials. Therefore, caution is recommended in case of co-administration.

Ketoconazole (200 mg daily), increased tadalafil (10 mg) single dose 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) single dose exposure (AUC) 4-fold and C_max by 22%.

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).

Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.

Tadalafil is not indicated for use by women.

There are limited data from the use of tadalafil in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. As a precautionary measure, it is preferable to avoid the use of tadalafil during pregnancy.

Tadalafil is not indicated for use by women.

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.

Fertility

Tadalafil is not indicated for use by women.

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.

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.

Erectile dysfunction / benign prostatic hyperplasia

Summary of the safety profile

The most commonly reported adverse reactions in patients taking tadalafil for the treatment of erectile dysfunction 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. The majority of headaches reported with tadalafil once-a-day dosing are experienced within the first 10 to 30 days of starting treatment.

Tabulated summary of adverse reactions

The table below lists the adverse reactions observed from spontaneous reporting and in placebocontrolled clinical trials (comprising a total of 8022 patients on tadalafil and 4422 patients on placebo) for on-demand and once-a-day treatment of erectile dysfunction and the once-a-day treatment of benign prostatic hyperplasia.

Frequency convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000) and not known (cannot be estimated from the available data).

¹ Most of the patients had pre-existing cardiovascular risk factors.
² Postmarketing surveillance reported adverse reactions not observed in placebo-controlled clinical trials.
³ More commonly reported when tadalafil is given to patients who are already taking antihypertensive medicinal products.

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 erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited. In clinical trials with tadalafil taken on demand for the treatment of erectile dysfunction, 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 benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age.

Pulmonary arterial hypertension (PAH), functional class II and III

Summary of the safety profile

The most commonly reported adverse reactions, occurring in ≥10% of patients in the tadalafil 40 mg treatment arm, were headache, nausea, back pain, dyspepsia, flushing, myalgia, nasopharingitis and pain in extremity. The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age.

In the pivotal placebo-controlled study of tadalafil for the treatment of PAH, a total of 323 patients were treated with tadalafil at doses ranging from 2.5 mg to 40 mg once daily and 82 patients were treated with placebo. The duration of treatment was 16 weeks. The overall frequency of discontinuation due to adverse events was low (tadalafil 11%, placebo 16%). Three hundred and fifty-seven (357) patients who completed the pivotal study entered a long-term extension study. Doses studied were 20 mg and 40 mg once daily.

Tabulated list of adverse reactions

The table below lists the adverse reactions reported during the placebo-controlled clinical trial in patients with PAH treated with tadalafil. Also included in the table are some adverse reactions which have been reported in clinical trials and/or post-marketing with tadalafil in the treatment of male erectile dysfunction. These events have either been assigned a frequency of "Not known," as the frequency in PAH patients cannot be estimated from the available data or assigned a frequency based on the clinical trial data from the pivotal placebo-controlled study of tadalafil.

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 (cannot be estimated from the available data).

¹ Events not reported in registration trials and cannot be estimated from the available data. The adverse reactions have been included in the table as a result of post-marketing or clinical trial data from the use of tadalafil in the treatment of erectile dysfunction.
² Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors.
³ Actual MedDRA terms included are abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and stomach discomfort.
⁴ Clinical non-MedDRA term to include reports of abnormal/excessive menstrual bleeding conditions such as menorrhagia, metrorrhagia, menometrorrhagia, or vaginal haemorrhage.
⁵ The adverse reactions have been included in the table as a result of post-marketing or clinical trial data from the use of tadalafil in the treatment of erectile dysfunction; and in addition, the frequency estimates are based on only 1 or 2 patients experiencing the adverse reaction in the pivotal placebo- controlled study of tadalafil.
⁶ Headache was the most commonly reported adverse reaction. Headache may occur at the beginning of therapy; and decreases over time even if treatment is continued.

Paediatric population

A total of 51 paediatric patients aged from 2.5 to 17 years with PAH were treated with tadalafil in clinical trials (H6D-MC-LVHV, H6D-MC-LVIG). A total of 391 paediatric patients with PAH, from new-born to <18 years, were treated with tadalafil in an observational post-marketing study (H6D-JE-TD01). Following tadalafil administration, the frequency, type and severity of adverse reactions in children and adolescents were similar to that seen for adults. Due to differences in study design, sample size, gender, age range, and doses, safety findings from these trials are detailed separately below.

Placebo-controlled clinical trial in paediatric patients (H6D-MC-LVHV)

In a randomised, placebo-controlled study in 35 patients aged 6.2 to 17.9 years (median age of 14.2 years) with PAH, a total of 17 patients were treated once daily with tadalafil 20 mg (middle-weight cohort, ≥25 kg to <40 kg) or 40 mg (heavy-weight cohort, ≥40 kg), and 18 patients were treated with placebo, for 24 weeks. The most common AEs, occurring in ≥ 2 patients treated with tadalafil, were headache (29.4%), upper respiratory tract infection and influenza (17.6% each), and arthralgia and epistaxis (11.8% each). No deaths or SAEs were reported. Of the 35 paediatric patients treated in the short-term, placebo-controlled study, 32 entered the 24 month long-term open-label extension and 26 patients completed the follow-up. No new safety signals were observed.

Uncontrolled pharmacokinetic study in paediatric patients (H6D-MC-LVIG)

In a paediatric multiple ascending dose study, 19 patients with a median age of 10.9 years [range 2.5 - 17 years] received once daily tadalafil, for an open-label treatment duration of 10 weeks (Period 1) and for up to a further 24 months in an extension (Period 2). SAEs were reported in 8 patients (42.1%). These were pulmonary hypertension (21.0%), viral infection (10.5%), and cardiac failure, gastritis, pyrexia, type 1 diabetes mellitus, febrile convulsion, presyncope, seizure, and ovarian cyst (5.3% each). No patient was discontinued due to AEs. TEAEs were reported in 18 patients (94.7%) and the most frequent TEAEs (occurring in ≥5 patients) were headache, pyrexia, viral upper respiratory tract infection, and vomiting. Two deaths were reported.

Post-marketing study in paediatric patients (H6D-JE-TD01)

Safety data were collected during an observational post-marketing study in Japan including 391 paediatric PAH patients (2 years maximum observational period). The mean age of patients in the study was 5.7 ± 5.3 years, including 79 patients aged <1 year, 41 aged 1 to <2 years, 122 aged 2 to 6 years, 110 aged 7 to 14 years, and 39 aged 15 to 17 years. AEs were reported in 123 patients (31.5%). The incidences of AEs (≥5 patients) were pulmonary hypertension (3.6%); headache (2.8%); heart failure and decreased platelet count (2.0% each); epistaxis and upper respiratory tract infection (1.8% each); bronchitis, diarrhoea, and abnormal hepatic function (1.5% each); and gastroenteritis, protein losing gastroenteropathy, and increased aspartate aminotransferase (1.3% each). The incidence of SAEs was 12.0% (≥3 patients), including pulmonary hypertension (3.6%), heart failure (1.5%), and pneumonia (0.8%). Sixteen deaths (4.1%) were reported; none were related to tadalafil.