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Actions of Tadlis in details

Pharmacotherapeutic Group: Drugs used in erectile dysfunction.

Pharmacology: Pharmacodynamics: Tadlis is a potent, 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 Tadlis 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. Tadlis has no effect in the absence of sexual stimulation. Studies in vitro have shown that Tadlis 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 Tadlis is more potent on PDE5 than on other phosphodiesterases. Tadlis is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and other organs. Tadlis 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, Tadlis is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadlis is also >9,000-fold more potent for PDE5 than for PDE7, 8, 9, and 10 and 14-fold more potent for PDE5 than for PDE11. The tissue distribution and physiological effects of the inhibition of PDE8 through PDE11 have not been elucidated.

Two clinical studies were conducted in 571 patients in an at-home setting to define the period of responsiveness to Tadlis. Tadlis 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. Sexual Encounter Profile (SEP) diary data collected in clinical studies supports this period of responsiveness. In these studies patients were free to choose the time interval between dose administration and the time of sexual attempts.

Tadlis 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. When Tadlis and certain oral antihypertensive medications were assessed in drug interaction studies, Tadlis did not result in clinically significant augmentation of the antihypertensive effects of those medications.

In a study to assess the effects of Tadlis 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 Tadlis 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%).

Tadlis at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 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 Tadlis improved their erections. Also, patients with erectile dysfunction in all severity categories reported improved erections while taking Tadlis (86%, 83% and 72% for mild, moderate, and severe, respectively). In the primary efficacy studies, 75% of intercourse attempts were successful in Tadlis-treated patients.

Studies on Spermatogenesis: Three studies were conducted in men to assess the potential effect on spermatogenesis of Tadlis 10 mg (one 6-month study) and 20 mg (one 6-monthand one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg Tadlis for 6 months and the study of 20 mg Tadlis for 9 months, results showed a decrease in mean sperm concentrations relative to placebo. This effect was not seen in the study of 20 mg Tadlis 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 with either 10 or 20 mg of Tadlis compared to placebo.

Pharmacokinetics: Absorption: Tadlis is rapidly absorbed after oral administration and the mean maximum observed plasma concentration (C_max) is achieved at a medium time of 2 hours after dosing. Absolute bioavailability of Tadlis following oral dosing has not been determined.

The rate and extent of absorption of Tadlis are not influenced by food, thus Tadlis 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 Tadlis is distributed into tissues. At therapeutic concentrations, 94% of Tadlis 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: Tadlis 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 Tadlis for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.

Elimination: The mean oral clearance for Tadlis is 2.5 L/h and the mean half-life is 17.5 hours in healthy subjects. Tadlis 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: Tadlis pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 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 or over), had a lower oral clearance of Tadlis, 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.

Patients with Diabetes: Tadlis 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.

Renal Insufficiency: In subjects with renal insufficiency, including those on hemodialysis, Tadlis exposure AUC was higher than in healthy subjects.

Hepatic Insufficiency: Tadlis exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B) is comparable to exposure in healthy subjects. No data are available in patients with severe hepatic impairment (Child-Pugh Class C).

Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential, toxicity to reproduction. There was no impairment of fertility in male and female rats. In dogs given Tadlis daily for 6 to 12 months at doses of 25 mg/kg/day and above, there were alterations to these miniferous tubular epithelium that resulted in a decrease in spermatogenesis in some dogs.

How should I take Tadlis?

Use Tadlis exactly as directed by your doctor. Do not use more of it and do not use it more often than your doctor ordered. If too much is used, the chance of side effects or other problems is increased.

Special patient instructions come with Tadlis. Read the directions carefully before you start using Tadlis and each time you get a refill of your medicine.

You may take Tadlis with or without food.

Swallow the Tadlis® tablet whole. Do not split, break, or crush it.

When using Tadlis for erectile dysfunction, the ability to have sexual activity may be improved for up to 36 hours after taking the tablet.

Use only the brand of Tadlis that your doctor prescribed. Different brands may not work the same way.

Dosing

The dose of Tadlis will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Tadlis. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For treatment of benign prostatic hyperplasia (daily use):
    • Adults—5 milligrams (mg) as a single dose, no more than once a day, taken at the same time each day.
    • Children—Use is not recommended.
  • For treatment of erectile dysfunction (as needed):
    • Adults—10 milligrams (mg) as a single dose, no more than once a day, taken 30 minutes before you think sexual activity may occur. Your doctor may adjust your dose if needed.
    • Children—Use is not recommended.
  • For treatment of erectile dysfunction (daily use):
    • Adults—2.5 milligrams (mg) once a day, taken at the same time each day, without regard for the timing of sexual activity. Your doctor may adjust your dose if needed.
    • Children—Use is not recommended.
  • For treatment of erectile dysfunction and benign prostatic hyperplasia (daily use):
    • Adults—5 milligrams (mg) once a day, taken at the same time each day, without regard for the timing of sexual activity.
    • Children—Use is not recommended.
  • For treatment of pulmonary arterial hypertension:
    • Adults—40 milligrams (mg) once a day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of Tadlis, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Tadlis administration

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Tadlis can be taken with or without food.

Do not break or split a Tadlis tablet. Swallow it whole.

Tadlis is usually taken only once per day. Follow your doctor's instructions. For erectile dysfunction, take the medicine just before sexual activity but not more than once per day.

Tadlis can help achieve an erection when sexual stimulation occurs. An erection will not occur just by taking a pill. Follow your doctor's instructions.

Tadlis is usually taken once per day. Follow your doctor's instructions. Do not take Tadlis for erectile dysfunction if you are taking Tadlis for pulmonary arterial hypertension.

Do not take Tadlis more than once a day. Allow 24 hours to pass between doses. If you take the medication daily, take it at the same time each day.

Contact your doctor or seek emergency medical attention if your erection is painful or lasts longer than 4 hours. A prolonged erection (priapism) can damage the penis.

Store at room temperature away from moisture and heat.

Tadlis pharmacology

Mechanism of Action

Tadlis is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by Tadlis increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.

Studies in vitro have demonstrated that Tadlis is a selective inhibitor of PDE5. PDE5 is found in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.

In vitro studies have shown that the effect of Tadlis is more potent on PDE5 than on other phosphodiesterases. These studies have shown that Tadlis is >10,000–fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadlis is >10,000–fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, Tadlis is 700–fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadlis is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadlis is 14–fold more potent for PDE5 than for PDE11A1 and 40–fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, Tadlis inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.

Pharmacodynamics

Effects on Blood Pressure When Administered with Nitrates

In clinical pharmacology studies, Tadlis (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Do not use Tadlis in patients taking any form of nitrates.

A double–blind, placebo–controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) assessed the interaction between nitroglycerin and Tadlis. Subjects received daily doses of Tadlis 20 mg or matching placebo for 7 days and then were given a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre–specified timepoints following their last dose of Tadlis (2, 4, 8, 24, 48, 72, and 96 hours after Tadlis). A significant interaction between Tadlis and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between Tadlis and NTG was not observed, although a few more Tadlis subjects compared to placebo experienced greater blood–pressure lowering effects at this timepoint. After 48 hours, the interaction was not detectable..

Effects on Blood Pressure

Tadlis 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively). In addition, there was no significant effect on heart rate.

Effects on Blood Pressure When Administered with Antihypertensives

Amlodipine — A study assessed the interaction between amlodipine (5 mg daily) and Tadlis 10 mg. There was no effect of Tadlis on amlodipine blood levels and no effect of amlodipine on Tadlis blood levels. The mean reduction in supine systolic/diastolic blood pressure because of Tadlis 10 mg in subjects taking amlodipine was 3/2 mm Hg, compared to placebo. In a similar study using Tadlis 20 mg, there were no clinically significant differences between Tadlis and placebo in subjects taking amlodipine.

Angiotensin II receptor blockers (with and without other antihypertensives) — A study assessed the interaction between angiotensin II receptor blockers and Tadlis 20 mg. Subjects in the study were taking any marketed angiotensin II receptor blocker, either alone, as a component of a combination product, or as part of a multiple antihypertensive regimen. Following dosing, ambulatory measurements of blood pressure revealed differences between Tadlis and placebo of 8/4 mm Hg in systolic/diastolic blood pressure.

Bendroflumethiazide — A study assessed the interaction between bendroflumethiazide (2.5 mg daily) and Tadlis 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure because of Tadlis 10 mg in subjects taking bendroflumethiazide was 6/4 mm Hg, compared to placebo.

Enalapril — A study assessed the interaction between enalapril (10 to 20 mg daily) and Tadlis 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure because of Tadlis 10 mg in subjects taking enalapril was 4/1 mm Hg, compared to placebo.

Metoprolol — A study assessed the interaction between sustained–release metoprolol (25 to 200 mg daily) and Tadlis 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure because of Tadlis 10 mg in subjects taking metoprolol was 5/3 mm Hg, compared to placebo.

Effects on Blood Pressure When Administered with Alcohol

Alcohol and PDE5 inhibitors, including Tadlis, are mild systemic vasodilators. The interaction of Tadlis with alcohol was evaluated in three clinical pharmacology studies. In two of these, alcohol was administered at a dose of 0.7 g/kg, which is equivalent to approximately 6 ounces of 80–proof vodka in an 80–kg male, and Tadlis was administered at a dose of 10 mg in one study and 20 mg in another. In both these studies, all patients imbibed the entire alcohol dose within 10 minutes of starting. In one of these two studies, blood alcohol levels of 0.08% were confirmed. In these two studies, more patients had clinically significant decreases in blood pressure on the combination of Tadlis and alcohol as compared to alcohol alone. Some subjects reported postural dizziness, and orthostatic hypotension was observed in some subjects. When Tadlis 20 mg was administered with a lower dose of alcohol (0.6 g/kg, which is equivalent to approximately 4 ounces of 80–proof vodka, administered in less than 10 minutes), orthostatic hypotension was not observed, dizziness occurred with similar frequency to alcohol alone, and the hypotensive effects of alcohol were not potentiated.

Tadlis did not affect alcohol plasma concentrations and alcohol did not affect Tadlis plasma concentrations.

Effects on Blood Pressure When Administered with Alpha-Blockers

Alpha-blockers and PDE5 inhibitors, including Tadlis, are systemic vasodilators. In subjects receiving concomitant Tadlis (20 mg single dose) and doxazosin (8 mg daily), an alpha-1 adrenergic receptor blocker, there was an augmentation of the blood pressure–lowering effect of doxazosin. This effect was still present at 12 hours postdose and had generally disappeared at 24 hours. The number of subjects with potentially clinically significant standing–blood–pressure decreases was greater for the combination.

An additional study was performed with Tadlis (20 mg single dose) and doxazosin (4 and 8 mg daily) using ambulatory blood pressure monitoring. The augmentation appeared unrelated to dosing times and resulted in a greater number of outliers for the combination than had been observed in the previous study. Both of these studies had some symptomatology associated with these blood pressure changes.

A further study was carried out with doxazosin (up to 4 mg daily) added to Tadlis (5 mg daily) and there was again an augmentation of response. In this clinical pharmacology study there were symptoms associated with the decrease in blood pressure, including syncope.

An interaction study with Tadlis (20 mg single dose) and alfuzosin, also an alpha-1 adrenergic receptor blocker, showed no clinically significant effect on blood pressure.

In two clinical pharmacology studies in healthy volunteers, Tadlis (5 mg daily, and 10 mg and 20 mg single dose) had no clinically significant effect on blood pressure changes because of tamsulosin, a selective alpha-1a adrenergic receptor blocking agent.

Effects on Cardiac Electrophysiology

The effect of a single 100 mg dose of Tadlis (2.5 times the recommended dose) on the QT interval was evaluated at the time of peak Tadlis concentration in a randomized, double–blinded, placebo, and active–controlled (intravenous ibutilide) crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for Tadlis, relative to placebo, was 3.5 milliseconds (two–sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for Tadlis, relative to placebo, was 2.8 milliseconds (two–sided 90% CI=1.2, 4.4). In this study, the mean increase in heart rate associated with a 100 mg dose of Tadlis compared to placebo was 3.1 beats per minute.

Effects on Exercise Stress Testing

The effects of Tadlis on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise–induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (Tadlis 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that Tadlis was similar to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received Tadlis followed by sublingual nitroglycerin in the post–exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by Tadlis of the blood–pressure–lowering effects of nitrates.

Effects on Vision

Single oral doses of PDE inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth–Munsell 100–hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of Tadlis 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with Tadlis, reports of changes in color vision were rare (<0.1% of patients).

Effects on Sperm Characteristics

Three studies were conducted in men to assess the potential effect on sperm characteristics of Tadlis 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 three studies. In the study of 10 mg Tadlis for 6 months and the study of 20 mg Tadlis for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg Tadlis taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of Tadlis compared to placebo.

Dose-Response Relationship

Dose-response relationships, between 20 mg and 40 mg, were not observed for 6-minute walk distance or pulmonary vascular resistance (PVR) in subjects with PAH in the placebo-controlled study. Median change from baseline in 6-minute walk distance was 32 meters and 35 meters at 16 weeks in subjects receiving 20 mg and 40 mg daily, respectively. Mean change from baseline PVR was -254 dynes*sec*cm-5 and -209 dynes*sec*cm-5 at 16 weeks in patients receiving 20 mg and 40 mg daily, respectively.

Pharmacokinetics

Over a dose range of 2.5 to 20 mg, Tadlis exposure (AUC) increases proportionally with dose in healthy subjects. In PAH patients administered between 20 and 40 mg of Tadlis, an approximately 1.5-fold greater AUC was observed indicating a less than proportional increase in exposure over the entire dose range of 2.5 to 40 mg. During Tadlis 20 and 40 mg once daily dosing, steady-state plasma concentrations were attained within 5 days, and exposure was approximately 1.3-fold higher than after a single dose.

Absorption — After single oral-dose administration, the maximum observed plasma concentration (Cmax) of Tadlis is achieved between 2 and 8 hours (median time of 4 hours). Absolute bioavailability of Tadlis following oral dosing has not been determined.

The rate and extent of absorption of Tadlis are not influenced by food; thus Tadlis may be taken with or without food.

Distribution — The mean apparent volume of distribution following oral administration is approximately 77 L, indicating that Tadlis is distributed into tissues. At therapeutic concentrations, 94% of Tadlis in plasma is bound to proteins.

Metabolism — Tadlis is predominantly metabolized by CYP3A to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

Elimination — Following 40 mg, the mean oral clearance for Tadlis is 3.4 L/hr and the mean terminal half-life is 15 hours in healthy subjects. In patients with pulmonary hypertension not receiving concomitant bosentan, the mean oral clearance for Tadlis is 1.6 L/hr, and the mean terminal half-life is 35 hours. Tadlis is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

Population pharmacokinetics — In patients with pulmonary hypertension not receiving concomitant bosentan, the average Tadlis exposure at steady-state following 40 mg was 26% higher when compared to those of healthy volunteers. The results suggest a lower clearance of Tadlis in patients with pulmonary hypertension compared to healthy volunteers.

Geriatric patients

In healthy male elderly subjects (65 years or over) after a 10 mg dose, a lower oral clearance of Tadlis, resulting in 25% higher exposure (AUC) with no effect on Cmax was observed relative to that in healthy subjects 19 to 45 years of age.

Renal impairment

In clinical pharmacology studies using single-dose Tadlis (5 to 10 mg), Tadlis exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg Tadlis, respectively. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to Tadlis or metabolite elimination.

Hepatic impairment

In clinical pharmacology studies, Tadlis exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of Tadlis in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C).

Patients with diabetes mellitus

In male patients with diabetes mellitus after a 10 mg Tadlis dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.

Race

Pharmacokinetic studies have included subjects from different ethnic groups, and no differences in the typical exposure to Tadlis have been identified. No dose adjustment is warranted.

Gender

In healthy female and male subjects following single and multiple-doses of Tadlis, no clinically relevant differences in exposure (AUC and Cmax) were observed. No dose adjustment is warranted.

Drug interaction studies

Tadlis is a substrate of and predominantly metabolized by CYP3A. Drugs that inhibit CYP3A can increase Tadlis exposure.

Ritonavir

Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A, CYP2C9, CYP2C19, and CYP2D6, increased Tadlis 20–mg single-dose exposure (AUC) by 32% with a 30% reduction in Cmax, relative to the values for Tadlis 20 mg alone. Ritonavir (200 mg twice daily), increased Tadlis 20–mg single-dose exposure (AUC) by 124% with no change in Cmax, relative to the values for Tadlis 20 mg alone. Ritonavir inhibits and induces CYP3A, the enzyme involved in the metabolism of Tadlis, in a time-dependent manner. The results suggest the initial inhibitory effect of ritonavir on CYP3A may be mitigated by a more slowly evolving induction effect so that after about 1 week of ritonavir twice daily, the exposure of Tadlis is similar in the presence of and absence of ritonavir. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase Tadlis exposure.

Other Cytochrome P450 inhibitors

CYP3A (e.g., ketoconazole) — Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A, increased Tadlis 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for Tadlis 20 mg alone. Ketoconazole (200 mg daily) increased Tadlis 10–mg single-dose exposure (AUC) by 107% and Cmax by 15%, relative to the values for Tadlis 10 mg alone.

Although specific interactions have not been studied, other CYP3A inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase Tadlis exposure.

Cytochrome P450 inducers

CYP3A (e.g., rifampin, bosentan) — Rifampin (600 mg daily), a CYP3A inducer, reduced Tadlis 10 mg single–dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for Tadlis 10 mg alone.

Bosentan (125 mg twice daily), a substrate of CYP2C9 and CYP3A and a moderate inducer of CYP3A, CYP2C9 and possibly CYP2C19, reduced Tadlis (40 mg once per day) systemic exposure by 42% and Cmax by 27% following multiple-dose co-administration.

Although specific interactions have not been studied, other CYP3A inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease Tadlis exposure.

Cytochrome P450 substrates — Tadlis is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms.

CYP1A2 (e.g., theophylline) — Tadlis (10 mg once per day) had no significant effect on the pharmacokinetics of theophylline. When Tadlis was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed.

CYP2C9 (e.g., warfarin) — Tadlis (10 mg and 20 mg once per day) had no significant effect on exposure (AUC) to S–warfarin or R–warfarin, nor did Tadlis affect changes in prothrombin time induced by warfarin.

CYP3A (e.g., midazolam, lovastatin or bosentan) — Tadlis (10 mg and 20 mg once per day) had no significant effect on exposure (AUC) to midazolam or lovastatin. Tadlis (40 mg once per day) had no clinically significant effect on exposure (AUC and Cmax) of bosentan, a substrate of CYP2C9 and CYP3A, or its metabolites.

Aspirin — Tadlis (10 mg and 20 mg once per day) did not potentiate the increase in bleeding time caused by aspirin.

P-glycoprotein (e.g., digoxin) — Coadministration of Tadlis (40 mg 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.

Combined oral contraceptives — At steady-state, Tadlis (40 mg once per day) increased ethinyl estradiol exposure (AUC) by 26% and Cmax by 70% relative to oral contraceptive administered with placebo. There was no significant effect of Tadlis on levonorgestrel.

Antacids — Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and Tadlis (10 mg) reduced the apparent rate of absorption of Tadlis without altering exposure (AUC) to Tadlis.

H2 antagonists (e.g., nizatidine) — An increase in gastric pH resulting from administration of nizatidine had no significant effect on Tadlis (10 mg) pharmacokinetics.

References

1. DailyMed. "TADALAFIL: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
2. NCIt. "Tadalafil: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
3. EPA DSStox. "Tadalafil: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

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