WARNINGS AND PRECAUTIONS

Tadalafil 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.

16.1 How Supplied

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionPenile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. 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. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation.The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues (e.g., adrenal cortex).

In vitro, tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range.

• For BPH, it relaxes smooth muscle in the prostate and bladder.
• Can be prescribed with other BPH medications like finasteride.
• May reduce the need for BPH-related surgery.
• Monitor for signs of allergic reaction: hives, swelling, difficulty breathing.
• In case of overdose, seek immediate medical attention.
• Overdose symptoms may include severe headache, vomiting.

The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.12.2 PharmacodynamicsEffects on

Blood PressureTadalafil 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

Comparing daily vs. as-needed tadalafil use

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 14 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 65 and over, while approximately 2 percent were 75 and over. In clinical pharmacology studies, tadalafil 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. [see Dosage and Administration ( 2.6) and Warnings and Precautions ( 5.8)] .

If you take more than the recommended amount of tadalafil

In clinical pharmacology studies erectile dysfunction pills tadalafil using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with creatinine clearance 30 to 80 mL/min. 10 OVERDOSAGE 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. In cases of overdose, standard supportive measures should be adopted as required. 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.

What should I do if I miss a dose of tadalafil?

Tadalafil has the empirical formula C 22H 19N 3O 4representing a molecular weight of 389.41. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.Tadalafil tablets, USP are available as almond-shaped tablets for oral administration. Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil, USP and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, iron oxide yellow, iron oxide red, ferrosoferric oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, polyvinyl alcohol-partially hydrolyzed, macrogol/PEG 3350 and lecithin (soya). It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol. Tadalafil tablets, USP are available as almond-shaped tablets for oral administration. in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively).

• Available as round, yellow, film-coated tablets imprinted with "10".
• Manufactured by various companies (e.g., Ajanta, Aurobindo, Teva).
• Generic tadalafil is bioequivalent to the brand-name drug.
• Check pill identification resources if unsure of medication.
• Report any suspected adverse reactions to the FDA or equivalent.
• Keep out of reach of children and pets.

In addition, there was no significant effect on heart rate.Effects on Blood Pressure When Administered with NitratesIn

What side effects can this medication cause?

No dose adjustment is warranted based on age alone. However, a greater sensitivity to medications in some older individuals should be considered. [see Clinical Pharmacology ( 12.3)] .8.6 Hepatic ImpairmentIn clinical pharmacology studies, tadalafil 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 tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C).

Eur Urol

[see Dosage and Administration ( 2.6) and Warnings and Precautions ( 5.8)] .8.7 Renal ImpairmentIn clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with creatinine clearance 30 to 80 mL/min. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in C maxand 2.7-to 4.8-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. 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 tadalafil or metabolite elimination. In a clinical pharmacology study (N=28) at a dose of 10 mg, back pain was reported as a limiting adverse event in male patients with creatinine clearance 30 to 50 mL/min.

As-Needed Dosage

At a dose of 5 mg, the incidence and severity of back pain was not significantly different than in the general population. In patients on hemodialysis taking 10-or 20-mg tadalafil, there were no reported cases of back pain. [see Dosage and Administration ( 2.6) and Warnings and Precautions ( 5.7)] . Tadalafil is 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. clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates.

• Tadalafil 10 mg should be taken approximately 30 minutes before intimacy.
• The medication’s maximum dosing frequency is once per day.
• Avoid grapefruit or grapefruit juice which can interact negatively.
• Blood pressure should be monitored during use if hypertensive.
• Do not use tadalafil if you have a retinal vascular disorder.
• Tadalafil can remain in your system for over a day.
• Patients with kidney or liver impairment should consult a doctor.
• It’s critical to follow prescribed dosing for safety.
• Reporting side effects like chest pain is essential.
• Tadalafil is not suitable for use with certain antidepressants.

Therefore, the use of tadalafil tablets in patients taking any form of nitrates is contraindicated [see Contraindications ( 4.1)] .A study was

conducted to assess the degree of interaction between nitroglycerin and tadalafil, should nitroglycerin be required in an emergency situation after tadalafil was taken.

7.1 Potential for Pharmacodynamic Interactions with Tadalafil Tablets

The mechanism for reducing BPH symptoms has not been established.Studies in vitrohave demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in the smooth muscle of the corpus cavernosum, prostate, and bladder as well as in vascular and visceral smooth muscle, skeletal muscle, urethra, platelets, kidney, lung, cerebellum, heart, liver, testis, seminal vesicle, and pancreas.In vitrostudies have shown that the effect of tadalafil is more potent on 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 PDE6, which is found in the retina and is responsible for phototransduction. This was 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) and receiving daily doses of tadalafil 20 mg or matching placebo for 7 days.

5.11 Combination with Other PDE5 Inhibitors or Erectile Dysfunction Therapies

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 (see Data). 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. 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. This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg.

It changes more than your penis

Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats. Tadalafil tablets are not indicated for use in females. There is no information on the presence of tadalafil and/or metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-fold greater than found in the plasma. Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months.

What are the dosage options for tadalafil?

There have been no studies evaluating the effect of tadalafil on fertility in men [see Clinical Pharmacology ( 12.2)] . Based on studies in animals, a decrease in spermatogenesis was observed in dogs, but not in rats [see Nonclinical Toxicology ( 13.1)] . 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 tablets 0.3 mg/kg, tadalafil tablets 0.6 mg/kg, or placebo daily for 48 weeks failed to demonstrate any benefit of treatment with tadalafil tablets on a range of assessments of muscle strength and performance.