Endobloc T

Ambrisentan (Endobloc T) is indicated for treatment of idiopathic (‘primary’) pulmonary arterial hypertension (IPAH) and pulmonary arterial hypertension (PAH) associated with connective tissue disease in patients with WHO functional class II or III symptoms. In the United States of America, Ambrisentan (Endobloc T) is also indicated in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. (WHO Group 1 Pulmonary arterial hypertension;)

Erectile Dysfunction

Tadalafil (Endobloc T) tablets are indicated for the treatment of erectile dysfunction (ED).

Benign Prostatic Hyperplasia

Tadalafil (Endobloc T) tablets are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

Erectile Dysfunction and Benign Prostatic Hyperplasia

Tadalafil (Endobloc T) tablets are indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH).

Limitation of Use

If Tadalafil (Endobloc T) tablets are used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of Tadalafil (Endobloc T) tablets decrease from 4 weeks until 26 weeks, and the incremental benefit of Tadalafil (Endobloc T) tablets beyond 26 weeks is unknown.

Ambrisentan (Endobloc T) prevents thickening of the blood vessels, especially those in the lungs and heart. Ambrisentan (Endobloc T) also lowers blood pressure in your lungs, helping your heart pump blood more efficiently.

Ambrisentan (Endobloc T) is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise and prevents your condition from getting worse.

Ambrisentan (Endobloc T) is available only under a special program called LEAP (Ambrisentan (Endobloc T) Education and Access Program). You must be registered in the program and sign agreements to use birth control and undergo pregnancy and blood testing as required by the program. Read all program brochures and agreements carefully.

Ambrisentan (Endobloc T) may also be used for purposes not listed in this medication guide.

Tadalafil (Endobloc T) is used to treat men who have erectile dysfunction (also called sexual impotence). Tadalafil (Endobloc T) belongs to a group of medicines called phosphodiesterase 5 (PDE5) inhibitors. These medicines prevent an enzyme called phosphodiesterase type-5 from working too quickly. The penis is one of the areas where this enzyme works.

Erectile dysfunction is a condition where the penis does not harden and expand when a man is sexually excited, or when he cannot keep an erection. When a man is sexually stimulated, his body's normal response is to increase blood flow to his penis to produce an erection. By controlling the enzyme, Tadalafil (Endobloc T) helps to maintain an erection after the penis is stroked by increasing blood flow to the penis. Without physical action to the penis, such as that occurring during sexual intercourse, Tadalafil (Endobloc T) will not work to cause an erection.

Tadalafil (Endobloc T) is also used to treat men who have signs and symptoms of benign prostatic hyperplasia (BPH). BPH is caused by an enlarged prostate. Men with BPH usually have difficulty urinating, a decreased flow of urination, hesitation at the beginning of urination, and a need to get up at night to urinate. Tadalafil (Endobloc T) will make these symptoms less severe and reduce the chance that prostate surgery will be needed. Tadalafil (Endobloc T) is also used to treat erectile dysfunction and signs and symptoms of BPH.

Tadalafil (Endobloc T) is also used in both men and women to treat the symptoms of pulmonary arterial hypertension. This is high blood pressure that occurs in the main artery that carries blood from the right side of the heart (the ventricle) to the lungs. When the smaller blood vessels in the lungs become more resistant to blood flow, the right ventricle must work harder to pump enough blood through the lungs. Tadalafil (Endobloc T) works on the PDE5 enzyme in the lungs to relax the blood vessels. This will increase the supply of blood to the lungs and reduce the workload of the heart.

Tadalafil (Endobloc T) is available only with your doctor's prescription..

Adult Dosage

Initiate treatment at 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, either the dose of Ambrisentan (Endobloc T) or tadalafil can be increased, as needed and tolerated, to Ambrisentan (Endobloc T) 10 mg or tadalafil 40 mg.

Do not split, crush, or chew tablets.

Pregnancy Testing In Females Of Reproductive Potential

Initiate treatment with Ambrisentan (Endobloc T) in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment.

How supplied

Dosage Forms And Strengths

5 mg and 10 mg film-coated tablets for oral administration

• Each 5 mg tablet is square convex, pale pink, with “5” on one side and “GSI” on the other side.
• Each 10 mg tablet is oval convex, deep pink, with “10” on one side and “GSI” on the other side.

Storage And Handling

Ambrisentan (Endobloc T) film-coated tablets are supplied as follows:

Store at 25° C (77° F); excursions permitted to 15–30° C (59–86° F). Store Ambrisentan (Endobloc T) in its original packaging.

Gilead Sciences, Inc., Foster City, CA 94404. Revised: October 2015

Do not split Tadalafil (Endobloc T) tablets; entire dose should be taken.

Tadalafil (Endobloc T) for Use as Needed for Erectile Dysfunction

• The recommended starting dose of Tadalafil (Endobloc T) 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 (Endobloc T) for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of Tadalafil (Endobloc T), this should be taken into consideration.

Tadalafil (Endobloc T) for Once Daily Use for Erectile Dysfunction

• The recommended starting dose of Tadalafil (Endobloc T) 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 (Endobloc T) dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability.

Tadalafil (Endobloc T) for Once Daily Use for Benign Prostatic Hyperplasia

• The recommended dose of Tadalafil (Endobloc T) for once daily use is 5 mg, taken at approximately the same time every day.
• When therapy for BPH is initiated with Tadalafil (Endobloc T) and finasteride, the recommended dose of Tadalafil (Endobloc T) for once daily use is 5 mg, taken at approximately the same time every day for up to 26 weeks.

Tadalafil (Endobloc T) for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia

The recommended dose of Tadalafil (Endobloc T) for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.

Use with Food

Tadalafil (Endobloc T) may be taken without regard to food.

Use in Specific Populations

Renal Impairment

Tadalafil (Endobloc T) for Use as Needed

• Creatinine clearance 30 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 (Endobloc T) for Once Daily Use

Erectile Dysfunction

• Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil (Endobloc T) for once daily use is not recommended.

Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia

• Creatinine clearance 30 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 (Endobloc T) for once daily use is not recommended.

Hepatic Impairment

Tadalafil (Endobloc T) 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 (Endobloc T) 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 (Endobloc T) is not recommended.

Tadalafil (Endobloc T) for Once Daily Use

• Mild or moderate (Child Pugh Class A or B): Tadalafil (Endobloc T) for once daily use has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if Tadalafil (Endobloc T) for once daily use is prescribed to these patients.
• Severe (Child Pugh Class C): The use of Tadalafil (Endobloc T) is not recommended.

Concomitant Medications

Nitrates

Concomitant use of nitrates in any form is contraindicated.

Alpha-Blockers

ED — When Tadalafil (Endobloc T) is coadministered with an alpha-blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and Tadalafil (Endobloc T) should be initiated at the lowest recommended dose.

BPH — Tadalafil (Endobloc T) is not recommended for use in combination with alpha-blockers for the treatment of BPH.

CYP3A4 Inhibitors

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

Tadalafil (Endobloc T) 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.

See also:
What is the most important information I should know about Ambrisentan (Endobloc T)?

Ambrisentan (Endobloc T) can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

If you are a woman of child-bearing potential, you will need to have a negative pregnancy test before you start treatment with Ambrisentan (Endobloc T). You will also be re-tested each month during your treatment.

You will be required to use two forms of birth control to prevent pregnancy during your treatment, and for at least 1 month after your treatment ends. If you have had a tubal ligation or are using a copper IUD, you will not need to use a second form of birth control.

Do not stop taking Ambrisentan (Endobloc T) without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Ambrisentan (Endobloc T) is available only under a special program called LEAP (Ambrisentan (Endobloc T) Education and Access Program). You must be registered in the program and sign agreements to use birth control and undergo pregnancy and blood testing as required by the program. Read all program brochures and agreements carefully.

See also:
What is the most important information I should know about Tadalafil (Endobloc T)?

5 mg Film-coated Tablet: Hypersensitivity to the active substance or to any of the excipients.

In clinical studies, Tadalafil (Endobloc T) was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and Tadalafil (Endobloc T) on the nitric oxide/cGMP pathway. Therefore, administration of Tadalafil (Endobloc T) to patients who are using any form of organic nitrate is contraindicated..

Tadalafil (Endobloc T), must not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.

20 mg Film-coated Tablet: Nitrates and Tadalafil (Endobloc T) must not be used concomitantly. Co-administration of Tadalafil (Endobloc T) with nitric oxide donors, organic nitrates or organic nitrites in any form either regularly or intermittently is contraindicated. Drugs which must not be used concomitantly include, but are not limited to, glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, nicorandil or organic nitrates in any form. In clinical studies, Tadalafil (Endobloc T) was shown to potentiate the hypotensive effects of both acute and chronic nitrate administration. This is thought to result from the combined effects of nitrates and Tadalafil (Endobloc T) on the nitric oxide/cGMP pathway.

Based on the results of a clinical study in which 150 subjects receiving daily doses of Tadalafil (Endobloc T) 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last Tadalafil (Endobloc T) dose. Thus, in a patient prescribed Tadalafil (Endobloc T), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of Tadalafil (Endobloc T) before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.

5 mg and 20 mg Film-coated Tablet: The following groups of patients with cardiovascular disease were not included in clinical trials and the use of Tadalafil (Endobloc T) is therefore contraindicated: Patients with 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; patients with a stroke within the last 6 months.

Tadalafil (Endobloc T) is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.

Tadalafil (Endobloc T) should not be used in patients with a known hypersensitivity to Tadalafil (Endobloc T) or to any ingredient of the tablet.

Use Ambrisentan (Endobloc T) as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Ambrisentan (Endobloc T) comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Ambrisentan (Endobloc T) refilled.
• Take Ambrisentan (Endobloc T) by mouth with or without food.
• Swallow Ambrisentan (Endobloc T) whole. Do not break, split, crush, or chew before swallowing.
• Take Ambrisentan (Endobloc T) on a regular schedule to get the most benefit from it. Taking Ambrisentan (Endobloc T) at the same times each day will help you to remember to take it.
• Continue to take Ambrisentan (Endobloc T) even if you feel well. Do not miss any doses.
• If you miss a dose of Ambrisentan (Endobloc T), take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Ambrisentan (Endobloc T).

Use Tadalafil (Endobloc T) as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Tadalafil (Endobloc T). Talk to your pharmacist if you have questions about this information.
• Take Tadalafil (Endobloc T) by mouth with or without food.
• Swallow Tadalafil (Endobloc T) whole. Do not break the tablet before swallowing.
• For use as needed: Take Tadalafil (Endobloc T) at least 30 minutes before sexual activity, as directed by your doctor. Tadalafil (Endobloc T) may work for up to 36 hours after you take it.
• For daily use: Take Tadalafil (Endobloc T) regularly at about the same time each day.
• Talk with your doctor if you have questions about how you should take Tadalafil (Endobloc T).
• Check with your doctor before you eat grapefruit or drink grapefruit juice while you are taking Tadalafil (Endobloc T).
• For use as needed: If you miss a dose of Tadalafil (Endobloc T) and you still intend to engage in sexual activity, take it as soon as you remember. Continue to take it as directed by your doctor. For daily use: If you miss a dose of Tadalafil (Endobloc T), take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses within the same day.

Ask your health care provider any questions you may have about how to use Tadalafil (Endobloc T).

Ambrisentan (Endobloc T) is used for the treatment of pulmonary arterial hypertension, a condition in which blood pressure rises due to narrowing of the arteries supplying blood from the heart to the lungs.

Tadalafil (Endobloc T) is used to treat high blood pressure in the lungs (pulmonary hypertension). It works by relaxing and widening the blood vessels in your lungs which allows the blood to flow more easily. Decreasing high blood pressure in the lungs allows your heart and lungs to work better and improves your ability to exercise.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

Tadalafil (Endobloc T) is also available in another brand for treating erectile dysfunction-ED in men. It may also be used to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia-BPH).

How to use Tadalafil (Endobloc T)

Read the Patient Information Leaflet provided by your pharmacist before you start taking Tadalafil (Endobloc T) and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

To treat high blood pressure in the lungs, take this medication by mouth as directed by your doctor, with or without food, usually once daily.

The dosage is based on your medical condition, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

Tell your doctor if your condition does not improve or if it worsens.

See also:
What other drugs will affect Ambrisentan (Endobloc T)?

Multiple dose coadministration of Ambrisentan (Endobloc T) and cyclosporine resulted in an approximately 2-fold increase in Ambrisentan (Endobloc T) exposure in healthy volunteers; therefore, limit the dose of Ambrisentan (Endobloc T) to 5 mg once daily when coadministered with cyclosporine.

See also:
What other drugs will affect Tadalafil (Endobloc T)?

Potential For Pharmacodynamic Interactions With Tadalafil (Endobloc T)

Nitrates

Administration of Tadalafil (Endobloc T) to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, Tadalafil (Endobloc T) was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken Tadalafil (Endobloc T), where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of Tadalafil (Endobloc T) 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 (Endobloc T), 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 coadministration of Tadalafil (Endobloc T) with doxazosin, tamsulosin or alfuzosin..

Antihypertensives

PDE5 inhibitors, including Tadalafil (Endobloc T), are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of Tadalafil (Endobloc T) on the potentiation of the bloodpressure- 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 (Endobloc T) with these agents compared with placebo..

Alcohol

Both alcohol and Tadalafil (Endobloc T), 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 (Endobloc T) can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil (Endobloc T) did not affect alcohol plasma concentrations and alcohol did not affect Tadalafil (Endobloc T) plasma concentrations..

Potential For Other Drugs To Affect Tadalafil (Endobloc T)

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Antacids

Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and Tadalafil (Endobloc T) reduced the apparent rate of absorption of Tadalafil (Endobloc T) without altering exposure (AUC) to Tadalafil (Endobloc T).

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 (Endobloc T) is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase Tadalafil (Endobloc T) exposure.

CYP3A4 (e.g., Ketoconazole)

Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased Tadalafil (Endobloc T) 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for Tadalafil (Endobloc T) 20 mg alone. Ketoconazole (200 mg daily) increased Tadalafil (Endobloc T) 10-mg singledose exposure (AUC) by 107% and Cmax by 15%, relative to the values for Tadalafil (Endobloc T) 10 mg alone.

Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase Tadalafil (Endobloc T) 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 (Endobloc T) 20-mg single-dose exposure (AUC) by 32% with a 30% reduction in Cmax, relative to the values for Tadalafil (Endobloc T) 20 mg alone. Ritonavir (200 mg twice daily), increased Tadalafil (Endobloc T) 20-mg single-dose exposure (AUC) by 124% with no change in Cmax, relative to the values for Tadalafil (Endobloc T) 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase Tadalafil (Endobloc T) exposure.

Cytochrome P450 Inducers

Studies have shown that drugs that induce CYP3A4 can decrease Tadalafil (Endobloc T) exposure.

CYP3A4 (e.g., Rifampin)

See also:
What are the possible side effects of Ambrisentan (Endobloc T)?

Clinically significant adverse reactions that appear in other sections of the labeling include:

• Embryo-fetal Toxicity
• Fluid Retention
• Pulmonary Edema with PVOD
• Decreased Sperm Count
• Hematologic Changes

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data for Ambrisentan (Endobloc T) are presented from two 12-week, placebo-controlled studies (ARIES-1 and ARIES-2) in patients with pulmonary arterial hypertension (PAH), and one randomized, double-blind, active-controlled trial in 605 patients with PAH (AMBITION) comparing Ambrisentan (Endobloc T) plus tadalafil to Ambrisentan (Endobloc T) or tadalafil alone. The exposure to Ambrisentan (Endobloc T) in these studies ranged from 1 day to 4 years (N=357 for at least 6 months and N=279 for at least 1 year).

In ARIES-1 and ARIES-2, a total of 261 patients received Ambrisentan (Endobloc T) at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The adverse reactions that occurred in > 3% more patients receiving Ambrisentan (Endobloc T) than receiving placebo are shown in Table 1.

Table 1 : Adverse Reactions with Placebo-Adjusted Rates > 3% in ARIES-1 and ARIES-2

Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent.

Few notable differences in the incidence of adverse reactions were observed for patients by age or sex. Peripheral edema was similar in younger patients ( < 65 years) receiving Ambrisentan (Endobloc T) (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients ( ≥ 65 years) receiving Ambrisentan (Endobloc T) (29%; 16/56) compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted cautiously.

The incidence of treatment discontinuations due to adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for Ambrisentan (Endobloc T) (2%; 5/261 patients) and placebo (2%; 3/132 patients). The incidence of patients with serious adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for placebo (7%; 9/132 patients) and for Ambrisentan (Endobloc T) (5%; 13/261 patients).

During 12-week controlled clinical trials, the incidence of aminotransferase elevations > 3 x upper limit of normal (ULN) were 0% on Ambrisentan (Endobloc T) and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause.

Combination Use with Tadalafil

The mean exposure to Ambrisentan (Endobloc T) + tadalafil in the AMBITION study was 78.7 weeks. The adverse reactions that occurred in > 5% more patients receiving Ambrisentan (Endobloc T) + tadalafil than receiving Ambrisentan (Endobloc T) or tadalafil monotherapy in AMBITION are shown in Table 2.

Table 2 : Adverse Reactions Reported More Commonly ( > 5%) on Ambrisentan (Endobloc T) + Tadalafil thanon Ambrisentan (Endobloc T) or Tadalafil Monotherapy (ITT) in AMBITION

Peripheral edema was more frequent on combination therapy; however, there was no notable difference observed in the incidence of peripheral edema in elderly patients ( ≥ 65 years) versus younger patients ( < 65 years) on combination therapy (44% vs. 45%) or Ambrisentan (Endobloc T) monotherapy (37% vs. 39%) in AMBITION.

Treatment discontinuations due to adverse events while on randomized treatment were similar across treatment groups: 16% for Ambrisentan (Endobloc T) + tadalafil, 14% for Ambrisentan (Endobloc T) alone, and 13% for tadalafil alone.

Use in Patients with Prior Endothelin Receptor Antagonist (ERA) Related Serum Liver Enzyme Abnormalities

In an uncontrolled, open-label study, 36 patients who had previously discontinued endothelin receptor antagonists (ERAs: bosentan, an investigational drug, or both) due to aminotransferase elevations > 3 x ULN were treated with Ambrisentan (Endobloc T). Prior elevations were predominantly moderate, with 64% of the ALT elevations < 5 x ULN, but 9 patients had elevations > 8 x ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and all eight had a recurrence of aminotransferase abnormalities that required discontinuation of ERA therapy. All patients had to have normal aminotransferase levels on entry to this study. Twenty-five of the 36 patients were also receiving prostanoid and/or phosphodiesterase type 5 (PDE5) inhibitor therapy. Two patients discontinued early (including one of the patients with a prior 8 x ULN elevation). Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks on Ambrisentan (Endobloc T) 5 mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the dose of Ambrisentan (Endobloc T) to 10 mg, no patients were discontinued for aminotransferase elevations. While the uncontrolled study design does not provide information about what would have occurred with re-administration of previously used ERAs or show that Ambrisentan (Endobloc T) led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that Ambrisentan (Endobloc T) may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal.

Postmarketing Experience

The following adverse reactions were identified during post-approval use of Ambrisentan (Endobloc T). Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate reliably the frequency or to establish a causal relationship to drug exposure: anemia requiring transfusion heart failure (associated with fluid retention), symptomatic hypotension, and hypersensitivity (e.g., angioedema, rash).

Elevations of liver aminotransferases (ALT, AST) have been reported with Ambrisentan (Endobloc T) use; in most cases alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure.

See also:
What are the possible side effects of Tadalafil (Endobloc T)?

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Tadalafil (Endobloc T) was administered to over 9000 men during clinical trials worldwide. In trials of Tadalafil (Endobloc T) for once daily use, a total of 1434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For Tadalafil (Endobloc T) for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively.

Tadalafil (Endobloc T) For Use As Needed For ED

In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the discontinuation rate due to adverse events in patients treated with Tadalafil (Endobloc T) 10 or 20 mg was 3.1%, compared to 1.4% in placebo treated patients.

When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported for Tadalafil (Endobloc T) for use as needed:

Table 1: Treatment-Emergent Adverse Reactions Reported by ≥ 2% of Patients Treated with Tadalafil (Endobloc T) (10 or 20 mg) and More Frequent on Drug than Placebo in the Eight Primary Placebo- Controlled Clinical Studies (Including a Study in Patients with Diabetes ) for Tadalafil (Endobloc T) for Us e as Needed for ED

Tadalafil (Endobloc T) For Once Daily Use For ED

In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82) and the discontinuation rate due to adverse events in patients treated with Tadalafil (Endobloc T) was 4.1%, compared to 2.8% in placebo-treated patients.

The following adverse reactions were reported in clinical trials of 12 weeks duration:

Table 2: Treatment-Emergent Adverse Reactions Reported by ≥ 2% of Patients Treated with Tadalafil (Endobloc T) for Once Daily Us e (2.5 or 5 mg) and More Frequent on Drug than Placebo in the Three Primary Placebo-Controlled Phase 3 Studies of 12 weeks Treatment Duration (Including a Study in Patients with Diabetes ) for Tadalafil (Endobloc T) for Once Daily Us e for ED

The following adverse reactions were reported over 24 weeks treatment duration in one placebo-controlled clinical study:

Table 3: Treatment-Emergent Adverse Reactions Reported by ≥ 2% of Patients Treated with Tadalafil (Endobloc T) for Once Daily Us e (2.5 or 5 mg) and More Frequent on Drug than Placebo in One Placebo-Controlled Clinical Study of 24 Weeks Treatment Duration for Tadalafil (Endobloc T) for Once Daily Use for ED

Tadalafil (Endobloc T) For Once Daily Use For BPH And For ED And BPH

In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with Tadalafil (Endobloc T) was 3.6% compared to 1.6% in placebo-treated patients. Adverse reactions leading to discontinuation reported by at least 2 patients treated with Tadalafil (Endobloc T) included headache, upper abdominal pain, and myalgia. The following adverse reactions were reported.

Table 4: Treatment-Emergent Adverse Reactions Reported by ≥ 1% of Patients Treated with Tadalafil (Endobloc T) for Once Daily Use (5 mg) and More Frequent on Drug than Placebo in Three Placebo- Controlled Clinical Studies of 12 Weeks Treatment Duration, including Two Studies for Tadalafil (Endobloc T) for Once Daily Us e for BPH and One Study for ED and BPH

Additional, less frequent adverse reactions ( < 1%) reported in the controlled clinical trials of Tadalafil (Endobloc T) for BPH or ED and BPH included: gastroesophageal reflux disease, upper abdominal pain, nausea, vomiting, arthralgia, and muscle spasm.

Back pain or myalgia was reported at incidence rates described in Tables 1 through 4. In Tadalafil (Endobloc T) clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia associated with Tadalafil (Endobloc T) treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. In general, pain was reported as mild or moderate in severity and resolved without medical treatment, but severe back pain was reported with a low frequency ( < 5% of all reports). When medical treatment was necessary, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective; however, in a small percentage of subjects who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all subjects treated with Tadalafil (Endobloc T) for on demand use discontinued treatment as a consequence of back pain/myalgia. In the 1-year open label extension study, back pain and myalgia were reported in 5.5% and 1.3% of patients, respectively. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no evidence of medically significant underlying pathology. Incidence rates for Tadalafil (Endobloc T) for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of Tadalafil (Endobloc T) for once daily use, adverse reactions of back pain and myalgia were generally mild or moderate with a discontinuation rate of < 1% across all indications.

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

Across all studies with any Tadalafil (Endobloc T) dose, reports of changes in color vision were rare ( < 0.1% of patients).

The following section identifies additional, less frequent events ( < 2%) reported in controlled clinical trials of Tadalafil (Endobloc T) for once daily use or use as needed. A causal relationship of these events to Tadalafil (Endobloc T) is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful:

Body as a Whole - asthenia, face edema, fatigue, pain, peripheral edema

Cardiovascular - angina pectoris, chest pain, hypotension, myocardial infarction, postural hypotension, palpitations, syncope, tachycardia

Digestive - abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, GGTP increased, loose stools, nausea, upper abdominal pain, vomiting, gastroesophageal reflux disease, hemorrhoidal hemorrhage, rectal hemorrhage

Musculoskeletal - arthralgia, neck pain

Nervous - dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo Renal and Urinary

Ambrisentan (Endobloc T) is an orally active selective type A endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension. It is approved in Europe, Canada and the United States for use as a single agent to improve exercise ability and delay clinical worsening. In addition, it is approved in the United States for use in combination with tadalafil to reduce the risks of disease progression, hospitalization and to improve exercise ability. Studies establishing the efficacy of Ambrisentan (Endobloc T) included patients with both idiopathic or heritable pulmonary arterial hypertension and those with pulmonary arterial hypertension associated with connective tissue diseases. Patients studied displayed symptoms and etiologies predominantly of WHO Functional Class II-III. As an endothelin receptor antagonist, Ambrisentan (Endobloc T) prevents endogenous endothelin peptide from constricting the muscles in blood vessels, allowing them to relax and permit a reduction in blood pressure.

Tadalafil (Endobloc T) is an orally adminstered drug used to treat male erectile dysfunction (impotence). It is marketed worldwide under the brand name Tadalafil (Endobloc T). It is a phosphodiesterase 5 (PDE5) inhibitor. Tadalafil (Endobloc T)'s distinguishing pharmacologic feature is its longer half-life (17.5 hours) compared with Viagra and Levitra (4-5 hours). This longer half-life results in a longer duration of action and is, in part, responsible for the Tadalafil (Endobloc T) nickname of the "weekend pill." This longer half-life also is the basis of current investigation for Tadalafil (Endobloc T)'s use in pulmonary arterial hypertension as a once-daily therapy. [Wikipedia]