Tadalafil

389.4

389.40

200-835-2

742SXX0ICT

759172|750236

DTXSID9046786

C47743

G04BE08|G - Genito urinary system and sex hormones

2934990002

74.9

2.3

white to beige

1.51±0.1 g/cm3(Predicted)

301-303 °C @ Solvent: Dichloromethane, Hexane

679.1±55.0 °C(Predicted)

2℃

1.705

Practically insoluble in water;DMSO: soluble 20mg/mL, clear

Hygroscopic, -20°C Freezer, Under Inert Atmosphere

2.2X10-14 mm Hg at 25 deg C /Estimated/

D20 +71.0°

Henry's Law constant = 5.0X10-18 atm-cu m/mol @ 25 °C /Estimated/

pKa = 0.85 /Estimated/

189.4 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|188.7 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 2.9X10-10 cu cm/molec-sec at 25 °C /Estimated/

UN 1648 3 / PGII

2

11-20/21/22-36

16-36/37

UQ4431050

F,Xn

P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P312, P321, P322, P330, P332+P313, P337+P313, P362, P363, P403+P233, P405, P501

H302

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl tadalafil, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (56.44%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P312, P321, P322, P330, P332+P313, P337+P313, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 101 companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Oral, Rat LD50 = 2000 mg/kg, no deaths or toxicity.

Despite fairly extensive use, tadalafil has been linked to only rare reports of serum aminotransferase elevations and clinically apparent liver injury. In a single case report, tadalafil was linked to cholestatic hepatitis arising within a few days of starting the medication. Immunoallergic features and autoantibodies were not present. The injury was self-limiting without residual evidence of bile duct injury. The related PDE5 inhibitor, sildenafil, has also been associated with rare cases of acute cholestatic liver injury with jaundice.

Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering the exposure (AUC) to tadalafil.|A significant interaction between tadalafil and nitroglycerin was observed to last up to 48 hours; at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered.|Administration of tadalafil to patients who are using any form of organic nitrates, either regularly and/or intermittently, is contraindicated; in clinical pharmacology studies tadalafil was shown to potentiate the hypotensive effects of nitrates; this is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway.|The safety and efficacy of combinations of tadalafil and other erectile dysfunctions have not been studied; use of combinations is not recommended.|For more Interactions (Complete) data for TADALAFIL (15 total), please visit the HSDB record page.

94%

Tadalafil's production and use in the treatment of erectile dysfunction(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 53,000(SRC), determined from a structure estimation method(2), indicates that tadalafil is expected to be immobile in soil(SRC). Volatilization of tadalafil from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.0X10-18 atm-cu m/mole(SRC), determined by a fragment constant estimation method(3). Tadalafil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.2X10-14 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 53,000(SRC), determined from a structure estimation method(2), indicates that tadalafil is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.0X10-18 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 2.5(SRC), from an estimated log Kow of 1.42(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tadalafil, which has an estimated vapor pressure of 2.2X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase tadalafil may be removed from the air by wet and dry deposition(SRC).

Tadalafil is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(1).

An estimated BCF of 2.5 was calculated for tadalafil(SRC), using an estimated log Kow of 1.42(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc for tadalafil can be estimated to be 53,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that tadalafil is expected to be immobile in soil.

The Henry's Law constant for tadalafil is estimated as 5.0X10-18 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that tadalafil is expected to be essentially nonvolatile from water surfaces(2). Tadalafil's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Tadalafil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.2X10-14 mm Hg(SRC), determined from a fragment constant method(3).

Occupational exposure to tadalafil may occur through inhalation and dermal contact with this compound at workplaces where tadalafil is produced or used. The general population is exposed via ingestion of tadalafil by its use as a drug. (SRC)

Used for the treatment of erectile dysfunction.|FDA Label|Adcirca is indicated in adults for the treatment of pulmonary arterial hypertension (PAH) classified as World Health Organization functional class II and III, to improve exercise capacity (see section 5.1).Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.|Treatment of erectile dysfunction.In order for tadalafil to be effective, sexual stimulation is required.Cialis is not indicated for use by women.|Treatment of erectile dysfunction in adult males.In order for tadalafil to be effective, sexual stimulation is required.Tadalafil Lilly is not indicated for use by women.Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males.|Treatment of erectile dysfunction in adult males.In order for tadalafil to be effective, sexual stimulation is required.Tadalafil Mylan is not indicated for use by women.|Talmanco is indicated in adults for the treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in idiopathic PAH (IPAH) and in PAH related to collagen vascular disease.|Treatment of pulmonary arterial hypertension

PDE5 Inhibitors

Tadalafil is indicated for the treatment of erectile dysfunction. /Included in US product labeling/

The Food and Drug Administration ... approved updated labeling for Cialis, Levitra and Viagra to reflect a small number of post-marketing reports of sudden vision loss, attributed to NAION (non arteritic ischemic optic neuropathy), a condition where blood flow is blocked to the optic nerve. FDA advises patients to stop taking these medicines, and call a doctor or healthcare provider right away if they experience sudden or decreased vision loss in one or both eyes. Further, patients taking or considering taking these products should inform their health care professionals if they have ever had severe loss of vision, which might reflect a prior episode of NAION. Such patients are at an increased risk of developing NAION again.|Cardiovascular status of patients should be considered since there is a degree of risk associated with sexual activity; treatments for erectile dysfunction, including tadalafil, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiac status.|The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for Cialis, and, therefore, the use of Cialis is not recommended in these groups until further information is available: patients with a 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 (<90/50 mm Hg), or uncontrolled hypertension (>170/100 mm Hg), and patients with a stroke within the last 6 months. In addition, 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.|The effect of a 100 mg single dose of tadalafil on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). A 100 mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with /this/ dose of tadalafil compared to placebo was 3.1 beats per minute.|For more Drug Warnings (Complete) data for TADALAFIL (18 total), please visit the HSDB record page.

Tadalafil is used to treat male erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH). Part of the physiological process of erection involves the release of nitric oxide (NO) in the corpus cavernosum. This then activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in the corpus cavernosum, resulting in increased inflow of blood and an erection. Tadalafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum. This means that, with tadalafil on board, normal sexual stimulation leads to increased levels of cGMP in the corpus cavernosum which leads to better erections. Without sexual stimulation and no activation of the NO/cGMP system, tadalafil should not cause an erection.

Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)|Compounds that specifically inhibit PHOSPHODIESTERASE 5. (See all compounds classified as Phosphodiesterase 5 Inhibitors.)|Drugs used in the treatment of urogenital conditions and diseases such as URINARY INCONTINENCE; PROSTATIC HYPERPLASIA; and ERECTILE DYSFUNCTION. (See all compounds classified as Urological Agents.)

After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.|Tadalafil 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).|63 L|oral cl=2.5 L/hr|Tmax: 30 minutes to 6 hours (median 2 hours). Absolute bioavailability has not been determined; rate and extent of absorption are not influenced by food.|Volume of distribution: 63 L; indicating distribution into tissues. Less than 0.0005% of administered dose was found in the semen of healthy subjects. 94% protein bound.|Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once-daily dosing, and exposure is approximately 1.6-fold greater than after a single dose.|Elimination: Mean oral clearance: 2.5 L per hour. Fecal: 61%. Urine: 36%.|For more Absorption, Distribution and Excretion (Complete) data for TADALAFIL (11 total), please visit the HSDB record page.

Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. In vitro data suggests the metabolites are not expected to be pharmacologically active at observed metabolite concentrations.|Biotransformation: Hepatic metabolism, mainly by CYP3A4. Tadalafil is predominantly metabolized by CYP3A4 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.

17.5 hours|Terminal: 17.5 hours

Penile erection during sexual stimulation is achieved by the relaxation of penile arteries and corpus cavernosal smooth muscles, leading to increased blood flow to the organ. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum, and is degraded by the cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum located around the penis. Tadalafil inhibits PDE5 and thereby enhances erectile function by increasing the amount of cGMP available.|In vitro studies have shown that the effect of tadalafil is more potent on phosphodiesterase type 5 (PDE5) than on other phosphodiesterases. These studies have shown that tadalafil 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. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE8, PDE9, PDE10 and 14-fold more potent for PDE5 than for PDE11A1, an enzyme found in human skeletal muscle. Tadalafil inhibits human recombinant PDE11A1 activity at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.|Studies in vitro have demonstrated that tadalafil is a selective inhibitor of phosphodiesterase type 5 (PDE5). PDE5 is found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.|Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosum smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic GMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cyclic GMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect on the absence of sexual stimulation.

In cases of overdose, standard supportive measures should be adopted as required. Hemodialysis contributes negligibly to tadalafil elimination.|A prolonged erection should be treated if it persists longer than 4 hours; priapism should be treated immediately. If priapism is not treated promptly, penile tissue damage and/or permanent loss of potency may result. Procedures for detumescence are listed below: Aspirate 40-60 mL of blood from either left or right corpora using vacutainer and holder for drawing blood. Apply ice for 20 minutes post aspiration if erection remains. If the above procedure is unsuccessful, put patient in supine position. Dilute phenylephrine... into... sterile water for injection. Using an insulin syringe, inject... /solution/ into the corpora every 2-5 minutes until detumescence occurs. Patients may develop transient bradycardia and hypertension due to phenylephrine injections. Monitor patient's blood pressure and pulse every 10 minutes. Patients with cardiac arrhythmia and diabetes may be at higher risk. Do not give phenylephrine to patients on MAO inhibitors. Phenylephrine is usually effective in the majority of patients if used within 12 hours of erection. If the above measures fail to detumesce the patient, consult a urologist as soon as possible. /Sildenafil/|Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

/SIGNS AND SYMPTOMS/ Single doses up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses.|/HUMAN EXPOSURE STUDIES/ Administration of tadalafil to patients who are using any form of organic nitrates, either regularly and/or intermittently, is contraindicated; in clinical pharmacology studies tadalafil was shown to potentiate the hypotensive effects of nitrates; this is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway.|/HUMAN EXPOSURE STUDIES/ Cardiovascular status of patients should be considered since there is a degree of risk associated with sexual activity; treatments for erectile dysfunction, including tadalafil, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiac status.|/HUMAN EXPOSURE STUDIES/ Left Ventricular Outflow Obstruction -- Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors.|For more Human Toxicity Excerpts (Complete) data for TADALAFIL (6 total), please visit the HSDB record page.

Cialis

Oral: Tablets, film-coated: 5 mg (Cialis), (Lilly ICOS); 10 mg (Cialis), (Lilly ICOS); 20 mg (Cialis), (Lilly ICOS).

Information available in 2005 indicated that Tadalafil was used in the manufacture of pharmaceutical preparations in the following countries: Argentina, Australia, Austria, Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Luxembourg, Netherlands, Norway, Portugal, Romania, Singapore, Spain, Sweden, Switzerland, United Kingdom, United States (1,2)

Human drugs -> Adcirca (previously Tadalafil Lilly) -> EMA Drug Category|Urologicals -> Human pharmacotherapeutic group|Human drugs -> Cialis -> EMA Drug Category|Human drugs -> Tadalafil Lilly -> EMA Drug Category|Human drugs -> Tadalafil Mylan -> EMA Drug Category|Human drugs -> Talmanco (previously Tadalafil Generics) -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients