Tadalafil (Dosing, Interaction, Side Effect, Administration, Etc..)

DRUG CLASS:
Antihypertensive
Erectile Dysfunction Agent
Phosphodiesterase Type 5 Inhibitor

DOSING:

Adult Dose

:
Important Note:
Orphan drug designation:
Treatment of Duchenne Muscular Dystrophy (DMD).
Treatment of pulmonary arterial hypertension.

Benign prostatic hyperplasia:

5 mg

orally once daily at the same time each day; for up to 26 weeks when

used with

finasteride for initiation of benign prostatic hyperplasia treatment.

Benign prostatic hyperplasia – Erectile dysfunction:

5 mg

ORALLY once daily at the same time each day

Erectile dysfunction:
(Once daily use) 2.5 mg ORALLY once daily at the same time each day; may increase to

5 mg

ORALLY once daily based on efficacy and tolerability.
(As needed use)

10 mg

ORALLY prior to anticipated sexual activity; may increase to

20 mg

ORALLY or decrease to

5 mg

ORALLY based on efficacy and tolerability; maximum frequency is once daily.

Pulmonary hypertension(FDA-LABELED INDICATION):
40 mg orally once daily with or without food (FDA dosage).
Switching from

sildenafil

: Take last dose of

sildenafil

in the evening and initiate

tadalafil

the next morning; for

sildenafil

60 mg or less given 3 times daily; initiate

tadalafil

at

20 mg

orally once daily and titrate to 40 mg once daily after 3 to 5 days; based on tolerability; for

sildenafil

80 to 100 mg 3 times daily; switch directly to

tadalafil 40 mg

once daily (off-label dosage).

Pediatric Dose

:
Important Note:
Orphan drug designation:
Treatment of Duchenne Muscular Dystrophy (DMD)
Treatment of pulmonary arterial hypertension

General Dosage Information:
Safety and efficacy not established in Pediatric patients younger than 18 years.

INDICATIONS:
FDA-LABELED INDICATIONS:
Benign prostatic hyperplasia
Benign prostatic hyperplasia - Erectile dysfunction
Erectile dysfunction
Pulmonary hypertension

NON-FDA LABELED INDICATIONS:
Secondary Raynaud phenomenon




MECHANISM OF ACTION:
(Benign prostatic hyperplasia)
Although the exact mechanism of action of

tadalafil

in benign prostatic hyperplasia is not known;

tadalafil

selectively inhibits phosphodiesterase type 5 (PDE5) and increases cyclic guanosine monophosphate (cGMP) levels. The smooth muscle cells of the prostate; bladder and surrounding vasculature also contain PDE5; inhibiting PDE5 and increasing cGMP levels in these tissues may cause smooth muscle relaxation; as observed in the corpus cavernosum and pulmonary arteries.

(Erectile dysfunction)
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 guanosine monophosphate (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 in the absence of sexual stimulation.

(Pulmonary hypertension)
The inhibition of phosphodiesterase type 5 (PDE5) by

tadalafil

increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed

ADVERSE EFFECT:
Common:
Dermatologic:
Flushing (1% to 13%).

Gastrointestinal:
Indigestion (1% to 13%)
Nausea (up to 11%)

Musculoskeletal:
Backache (2.4% to 12%)
Myalgia (1% to 14%)

Neurologic:
Headache (3% to 42%)

Respiratory:
Nasopharyngitis (2% to 13%)
Respiratory tract infection (3% to 13%)

Serious:
Cardiovascular:
Angina pectoris (less than 2%)
Chest pain (less than 2%)
Heart failure; Myocardial infarction (less than 2%)
Tachycardia (less than 2%)

Dermatologic:
Stevens-Johnson syndrome.

Neurologic:
Cerebral hemorrhage
Cerebrovascular accident
Seizure

Ophthalmic:
Anterior ischemic optic neuropathy
Non-arteritic
Retinal artery occlusion
Thrombosis of retinal vein

Otic:
Decreased hearing
Sudden onset (less than 2%)
Sudden hearing loss (less than 2%)

CONTRAINDICATION:
Concomitant

use

of nitrates (any form) either regularly or intermittently.
Concomitant

use

with a guanylate cyclase stimulator (eg; riociguat)
Known serious hypersensitivity to

tadalafil

; Stevens-Johnson syndrome and exfoliative dermatitis have been reported

DRUG INTERACTION:
Nitrates:
Administration of

tadalafil

to patients who are using any form of organic nitrate is contraindicated. In clinical pharmacology studies;

tadalafil

was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken

tadalafil

; where nitrate administration is deemed medically necessary in a life-threatening situation; at least 48 hours should elapse after the last

dose

of

tadalafil

before nitrate administration is considered. In such circumstances; nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.

Alpha-Blockers:
Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors; including

tadalafil

, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are

used in

combination; an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with co-administration of

tadalafil

with doxazosin; tamsulosin or alfuzosin.

Antihypertensives:
PDE5 inhibitors; including

tadalafil

; are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of

tadalafil

on the potentiation of the blood-pressure-lowering effects of selected antihypertensive medications (amlodipine; angiotensin II receptor blockers; bendrofluazide; enalapril; and metoprolol). Small reductions in blood pressure occurred following coadministration of

tadalafil

with these agents compared with placebo.

Alcohol:
Both alcohol and

tadalafil

; a PDE5 inhibitor; act as mild vasodilators. When mild vasodilators are taken in combination; blood-pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g.; 5 units or greater) in combination with

tadalafil

can increase the potential for orthostatic signs and symptoms; including increase in heart rate; decrease in standing blood pressure; dizziness; and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect

tadalafil

plasma concentrations.

Antacids:
Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to

tadalafil

.

H2 Antagonists (e.g. Nizatidine):
An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.

Cytochrome P450 Inhibitors:
TADALAFIL is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure.

CYP3A4 (e.g., Ketoconazole):
Ketoconazole (400 mg daily); a selective and potent inhibitor of CYP3A4; increased

tadalafil 20 mg

single-

dose

exposure (AUC) by 312% and Cmax by 22%; relative to the values for

tadalafil 20 mg

alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-

dose

exposure (AUC) by 107% and Cmax by 15%; relative to the values for

tadalafil 10 mg

alone .Although specific interactions have not been studied; other CYP3A4 inhibitors; such as erythromycin; itraconazole; and grapefruit juice; would likely increase tadalafil exposure

HIV Protease inhibitor:
Ritonavir (500 mg or 600 mg twice daily at steady state); an inhibitor of CYP3A4; CYP2C9; CYP2C19 and CYP2D6; increased

tadalafil

20-mg single-

dose

exposure (AUC) by 32% with a 30% reduction in Cmax; relative to the values for

tadalafil 20 mg

alone. Ritonavir (200 mg twice daily); increased

tadalafil

20-mg single-

dose

exposure (AUC) by 124% with no change in Cmax; relative to the values for

tadalafil 20 mg

alone. Although specific interactions have not been studied; other HIV protease inhibitors would likely increase

tadalafil

exposure.

Cytochrome P450 Inducers:
Studies have shown that drugs that induce CYP3A4 can decrease

tadalafil

exposure. CYP3A4 (e.g. Rifampin) — Rifampin (600 mg daily); a CYP3A4 inducer; reduced

tadalafil

10-mg single-

dose

exposure (AUC) by 88% and Cmax by 46%, relative to the values for

tadalafil 10 mg

alone. Although specific interactions have not been studied; other CYP3A4 inducers; such as carbamazepine; phenytoin; and Phenobarbital; would likely decrease

tadalafil

exposure. No

dose

adjustment is warranted. The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of

tadalafil

for once daily use; the magnitude of decreased efficacy is unknown.

Aspirin:
Tadalafil did not potentiate the increase in bleeding time caused by aspirin.

Cytochrome P450 Substrates:

Tadalafil

is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2; CYP3A4; CYP2C9; CYP2C19; CYP2D6; and CYP2E1.

CYP1A2 (e.g. Theophylline):
Tadalafil had no significant effect on the pharmacokinetics of theophylline. When tadalafil 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):
Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin; nor did

tadalafil

affect changes in prothrombin time induced by warfarin.

CYP3A4 (e.g. Midazolam or Lovastatin):
Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin.

P-glycoprotein (e.g. Digoxin):
Co-administration of

tadalafil

(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

PHARMACOKINETICS:
Absorption:
Maximum Plasma concentration(Tmax)
Oral: 2 to 4 hours

Bioavailability:
Oral: well-absorbed

Effect of Food:
no effect on absorption.

Distribution:
Volume of Distribution(Vd):
63 L to 77 L

Plasma Protein binding: 94%
Metabolism:
Hepatic: via CYP3A4

Excretion:
Renal: 36%
Fecal: 61%

Elimination:
15 to 35 hours

PRECAUTION:
Cardiovascular:
Underlying cardiovascular disease may be aggravated due to sexual activity or vasodilatory effects of

tadalafil

Patients with severely impaired autonomic control of blood pressure or left ventricular outflow obstruction (eg; aortic stenosis; idiopathic hypertrophic subaortic stenosis) may have an increased sensitivity to vasodilators

Use

not recommended in patients with veno-occlusive disease

Use

not recommended in patients with angina occurring during sexual intercourse or unstable angina; uncontrolled arrhythmias; hypotension (less than 90/50 mmHg); uncontrolled hypertension; heart failure (NYHA Class 2 or greater) in the last 6 months; or myocardial infarction within the last 90 days

Hematologic:
Patients with bleeding disorders or active peptic ulceration may experience increased bleeding times

Hepatic:
Mild or moderate hepatic impairment (Child Pugh Class A or B);

dose

adjustment may be necessary.
Severe hepatic impairment (Child Pugh Class C); avoid use.

Neurologic:

Use

in patients who experienced a stroke within the last 6 months not recommended.

Ophthalmic:
Sudden vision loss has been reported with phosphodiesterase type 5 (PDE5) inhibitors; drug discontinuation recommended

Use

not recommended in patients with hereditary degenerative retinal disorders; including retinitis Pigmentosa.

Otic:
Sudden hearing decrease or loss has been reported; drug discontinuation recommended

Renal:
Mild or moderate renal impairment (CrCl 31 and 80 mL/min);

dose

adjustment recommended.
Severe renal impairment (CrCl less than 30 mL/min or on hemodialysis)
CrCl less than 50 mL/min or ESRD on hemodialysis;

tadalafil

(R)

dose

adjustment recommended for on-demand use
CrCl 30 to 50 mL/min;

Dose

adjustment recommended for daily use

Reproductive:
Priapism or prolonged erections lasting greater than 4 hours have been rarely reported;

use

caution in patients with conditions that predispose them to priapism (eg; sickle cell anemia; multiple myeloma; or leukemia) or with anatomical deformation of the penis (eg; angulation; cavernosal fibrosis)

Concomitant Use:
Avoid

use

when initiating ritonavir
Avoid ;

use

with potent CYP3A inhibitors (eg; itraconazole; ketoconazole) or potent CYP3A inducers (eg; rifampin)

Use

with other phosphodiesterase type 5 (PDE5) inhibitors or erectile dysfunction therapies not recommended

Use

with alpha blockers not recommended

PREGNANCY CATEGORY:
Fetal Risk Cannot be ruled out

BREASTFEEDING:
Infant Risk Cannot be Ruled out

MONITORING:
Erectile dysfunction:
Improvement in quality and maintenance of an erection or ability to initiate (vaginal penetration) and complete sexual intercourse are indicative of efficacy

Pulmonary arterial hypertension:
Improvement in timed walking distance and exercise ability may indicate efficacy

Benign prostatic hypertrophy:
Improvement in signs and symptoms is indicative of efficacy

HOW TO TAKE OR ADMINISTRATION:
Oral:
May be taken with or without food
Do not split

Tadalafil tablets

; take entire

dose

DOSAGE FORM:
Oral Tablets:
20mg
5mg
10mg

TREATMENTS:
MANAGEMENT OF MILD TO MODERATE TOXICITY:
Limited data. Tadalafil overdoses are likely to require only supportive care; there is no specific treatment. Treat headache, facial flushing, dizziness and general weakness with IV fluids. Hypotension and tachycardia are anticipated to be generally mild and well tolerated and usually respond to IV fluids. Infuse IV NaCL 10 to 20 mL/kg, as needed.

MANAGEMENT OF SEVERE TOXICITY:
Treatment is symptomatic and supportive. Reflex tachycardia is usually seen due to hypotension. Patients with persistent hypotension despite intravenous fluids require vasopressors, theoretically alpha agonists norepinephrine and phenylephrine may be more effective.

TOXICOLOGY:
Limited data. A toxic

dose

has not been established. Single

doses

of 500 mg and daily

doses

of 100 mg were well tolerated in healthy volunteers.

PATIENT COUNSELING OR CLINICAL TEACHING:
Instruct patient to report symptoms of angina; palpitations; or tachycardia; and to refrain from further sexual activity or exercise
Advise patient to seek emergency treatment for prolonged erections or priapism.

Side effects

may include headache; dyspepsia; back pain; myalgia; nasopharyngitis; cough; and flushing
Counsel patient to report a sudden loss of vision or hearing
Advise patient to avoid excessive alcohol

use

(5 units or more) due to potential for orthostatic effects




Disclaimer:
For the Registered Medical Practitioner Only. We are not recommended for self medication. self medication is may harmful for health. We are only information about medicine.