ERIXIUM

Tadalafil is a selective phosphodiesterase-5 inhibitor that is used in the treatment of erectile dysfunction (ED), pulmonary arterial hypertension (PAH), and benign prostatic hypertrophy. 8, 9 It was first approved in by the FDA for use in ED and later in for PAH.

In contrast to other

PDE5 inhibitors like sildenafil, tadalafil has greater selectivity for PDE5 and a longer half-life which has made it a more suitable option for chronic once-daily dosing in the treatment of PAH.

Tadalafil is indicated for the treatment of erectile dysfunction (ED) and either alone or in combination with finasteride for the treatment of benign prostatic hypertrophy (BPH). 7, 11 It is also indicated for the treatment of pulmonary arterial hypertension (PAH) both alone and in combination with macitentan or other endothelin-1 antagonists. 8, 9,

Tadalafil exerts a therapeutic effect in

ED by increasing sexual stimulation-dependant smooth muscle relaxation in the penis, allowing the corpus cavernosum to fill with blood to produce an erection. 2, 3 Smooth muscle relaxation in the pulmonary vasculature helps to produce vasodilation in PAH which reduces blood pressure in the pulmonary arteries.

In BPH, tadalafil may contribute to decreased smooth muscle cell proliferation which may reduce the size of the prostate and relieve the anatomical obstruction which produces urinary symptoms of BPH.

The decreased affinity of tadalafil for

PDE6 compared to other PDE5 inhibitors may explain the reduced incidence of visual side effects. 8, 9, 2.

cGMP-specific 3',5'-cyclic phosphodiesterase Inhibitor.

Tadalafil has a tmax of 0.5-6h with a median of 2h in healthy adults. 1, 7 The tmax in adults with PAH is reported as 2-8h with a median of 4h.

There does not appear to be a significant effect on absorption when tadalafil is taken with food.

Tadalafil has a mean apparent volume of distribution of 63 L in healthy adults. 1, 7 The mean apparent volume of distribution is reported as 77 L in adults with PAH.

Tadalafil undergoes hepatic metabolism via

CYP3A4 to a catechol metabolite. 1, 5, 7, 8 This catechol metabolite undergoes subsequent methylation and glucuronidation with the methyl-glucuronide metabolite becoming the primary metabolite in circulation.

None of the known metabolites are considered to be active.

Hover over products below to view reaction partners Tadalafil Tadalafil catechol metabolite Tadalafil methylcatechol metabolite Tadalafil methylcatechol glucuronide metabolite.

Tadalafil is primarily eliminated via hepatic metabolism. 1, 7, 8 These metabolites are mainly excreted in the feces (61%) and to a lesser extent in the urine (36%).

The mean half-life of elimination of tadalafil is 15-17.5h in healthy adults. 1, 7, 8 The mean half-life of elimination in adults with PAH is reported as 35h.

The mean apparent oral clearance of tadalafil is 2.5-3.4 L/h in healthy adults. 1, 7, 8 The mean apparent oral clearance in adults with PAH is reported as 3.5 L/h.

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Symptoms of overdose are expected to be similar to typical adverse effects which may include headache, dyspepsia, back pain, myalgia, nasopharyngitis, and dizziness. 7, 8 Standard supportive care is recommended.

Hemodialysis is not expected to contribute significantly to tadalafil clearance.

Administration of tadalafil tablets to patients using any form of organic nitrate is contraindicated.

Tadalafil was shown to potentiate the hypotensive effect of nitrates.

History of known serious hypersensitivity reaction to tadalafil or ADCIRCA ® .

Administration with guanylate cyclase (GC) stimulators, such as riociguat. 4.1 Nitrates Administration of tadalafil tablets to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated.

In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates. 4.2 Hypersensitivity Reactions Tadalafil tablets are contraindicated in patients with a known serious hypersensitivity to tadalafil (tadalafil tablets or ADCIRCA ® ).

Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis. 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use tadalafil tablets in patients who are using a GC stimulator, such as riociguat.

PDE5 inhibitors, including tadalafil may potentiate the hypotensive effects of GC stimulators.

Do not split tadalafil tablets; entire dose should be taken.

Tadalafil tablets for use as needed

ED: Starting dose: 10 mg as needed prior to sexual activity.

Increase to 20 mg or decrease to 5 mg based upon efficacy/tolerability.

Improves erectile function compared to placebo up to 36 hours post dose.

Not to be taken more than once per day.

Tadalafil tablets for once daily use

ED: 2.5 mg taken once daily, without regard to timing of sexual activity.

May increase to 5 mg based upon efficacy and tolerability.

BPH: 5 mg, taken at approximately the same time every day ED and BPH: 5 mg, taken at approximately the same time every day Tadalafil tablets may be taken without regard to food. 2.1 Tadalafil Tablets for Use as Needed for Erectile Dysfunction The recommended starting dose of tadalafil tablets for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity.

The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability.

The maximum recommended dosing frequency is once per day in most patients.

Tadalafil tablets for use as needed were shown to improve erectile function compared to placebo up to 36 hours following dosing.

Therefore, when advising patients on optimal use of tadalafil tablets, this should be taken into consideration. 2.2 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction The recommended starting dose of tadalafil tablets for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.

The tadalafil tablets dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability. 2.3 Tadalafil Tablets for Once Daily Use for Benign Prostatic Hyperplasia The recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day. When therapy for BPH is initiated with tadalafil and finasteride, the recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day for up to 26 weeks. 2.4 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia The recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity. 2.5 Use with Food Tadalafil tablets may be taken without regard to food. 2.6 Use in Specific Populations Renal Impairment Tadalafil Tablets for Use as Needed Creatinine clearance to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours.

Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours.

Tadalafil Tablets for Once Daily Use Erectile Dysfunction Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablets for once daily use is not recommended.

Dysfunction/Benign Prostatic Hyperplasia Creatinine clearance to 50 mL/min: A starting dose of 2.5 mg is recommended.

An increase to 5 mg may be considered based on individual response.

Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablets for once daily use is not recommended.

Hepatic Impairment Tadalafil tablets for Use as Needed Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day. The use of tadalafil tablets once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised.

Severe (Child Pugh Class C): The use of tadalafil tablets is not recommended.

Tadalafil tablets for Once Daily Use

Mild or moderate (Child Pugh Class A or B): Tadalafil tablets for once daily use has not been extensively evaluated in patients with hepatic impairment.

Therefore, caution is advised if tadalafil tablets for once daily use is prescribed to these patients.

Severe (Child Pugh Class C): The use of tadalafil tablet is not recommended. 2.7 Concomitant Medications Nitrates Concomitant use of nitrates in any form is contraindicated.

ED —When tadalafil tablets are co-administered with an alpha-blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and tadalafil tablets should be initiated at the lowest recommended dose.

BPH — Tadalafil tablets are not recommended for use in combination with alpha-blockers for the treatment of BPH.

CYP3A4 Inhibitors Tadalafil tablets for Use as Needed — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of tadalafil tablets is 10 mg, not to exceed once every 72 hours.

Tadalafil tablets for Once Daily

Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 2.5 mg.

50090-7315 NDC: 50090-7315-0 90 TABLET, FILM COATED in a BOTTLE.

Tadalafil tablets are not indicated for use in females.

There are no data with the use of tadalafil tablets in pregnant women to inform any drug-associated risks for adverse developmental outcomes.

In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day.

Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given orally to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis.

In a prenatal/postnatal developmental study in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 10 times the MRHD based on AUC.

Signs of maternal toxicity occurred at doses greater than 16 times the MRHD based on AUC.

Surviving offspring had normal development and reproductive performance.

In another rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed.

The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg. Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.

Tadalafil tablets are not indicated for use in pediatric patients.

Safety and efficacy in patients below the age of 18 years have not been established.

A randomized, double-blind, placebo-controlled trial in pediatric patients (7 to 14 years of age) with Duchenne muscular dystrophy, who received tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily for 48 weeks failed to demonstrate any benefit of treatment with tadalafil on a range of assessments of muscle strength and performance.

No adverse effects were observed in a study in which tadalafil was administered orally at doses of 60, 200, and 1000 mg/kg/day to juvenile rats on postnatal days to 90.

The highest plasma tadalafil exposures (AUC) achieved were approximately 10-fold that observed at the MRHD.

Of the total number of subjects in ED clinical studies of tadalafil, approximately 19 percent were and over, while approximately 2 percent were and over.

Of the total number of subjects in BPH clinical studies of tadalafil (including the ED/BPH study), approximately 40 percent were over 65, while approximately 10 percent were and over.

In these clinical trials, no overall differences in efficacy or safety were observed between older (>65 and ≥75 years of age) and younger subjects (≤65 years of age).

However, in placebo-controlled studies with tadalafil tablets for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with tadalafil tablets (2.5% of patients) .

No dose adjustment is warranted based on age alone.

However, a greater sensitivity to medications in some older individuals should be considered. .