Tadalafil for pulmonary hypertension Adcirca, Talmanco

Tadalafil Tablets (Pulmonary Hypertension)

TADALAFIL (tah DA la fil) treats pulmonary arterial hypertension (PAH), a condition that causes high blood pressure in the lungs. It works by relaxing your blood vessels and lowering the blood pressure in your lungs, which makes it easier for your heart to pump blood to the rest of your body. It can also help you breathe easier and be more active.

This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my care team before I take this medication?

They need to know if you have any of these conditions:

How should I use this medication?

Take this medication by mouth with a glass of water. Follow the directions on the prescription label. You can take this medication with or without food. Take your medication at regular intervals. Take both tablets at the same time, one after the other. Do not split your dose throughout the day. Do not take it more often than directed. Do not stop taking except on your care team’s advice.

Talk to your care team about the use of this medication in children. Special care may be needed.

Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.

NOTE: This medicine is only for you. Do not share this medicine with others.

What if I miss a dose?

If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

What may interact with this medication?

Do not take this medication with any of the following:

This medication may also interact with the following:

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medication?

Do not change the dose of your medication without asking your care team. Call your care team if your medication is not working for you. This may be a sign that your condition has become worse.

If you notice any changes in your vision while taking this medication, call your care team as soon as possible. Stop using this medication and call your health care provider right away if you have a loss of sight in one or both eyes.

For males, contact you care team right away if an erection lasts longer than 4 hours or if it becomes painful. This may be a sign of serious problem and must be treated right away to prevent permanent damage.

If you experience symptoms of nausea, dizziness, chest pain, or arm pain after taking this medication, you should discuss the episode with your care team as soon as possible.

Do not drink more than 4 alcohol-containing drinks in a short period of time when taking this medication. When taken in excess, alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate or lowering your blood pressure.

What side effects may I notice from receiving this medication?

Side effects that you should report to your care team as soon as possible:

Side effects that usually do not require medical attention (report to your care team if they continue or are bothersome):

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medication?

Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Throw away any unused medication after the expiration date.

NOTE: This sheet is a summary. It may not cover all possible information. If you have questions about this medicine, talk to your doctor, pharmacist, or health care provider.

Tadalafil for pulmonary hypertension Adcirca, Talmanco

When you collect your prescriptions, check that you have been given the same brand of tablets as before. If the appearance is not the same as usual, speak with your doctor or pharmacist.

The usual dose is 40 mg daily (taken as two 20 mg tablets).

The most common side-effects are headache, flushing, nasal congestion, stomach upset, and muscle aches and pains.

Tadalafil for pulmonary hypertension

Adcirca, Talmanco
In this article

About tadalafil for pulmonary hypertension

Primary pulmonary hypertension is a rare condition where there is too high a blood pressure in the blood vessels that supply your lungs from your heart.

Tadalafil relaxes the muscle cells in the walls of the blood vessels to your lungs, allowing them to become wider (dilated). This reduces the pressure in these blood vessels and allows blood to flow more easily through them. In turn, this increases the supply of blood to your lungs and improves your ability to do physical activities. It will be prescribed for you by a specialist doctor.

Tadalafil can also be prescribed for men with two completely different conditions – please see the separate medicine leaflet called Tadalafil for erectile dysfunction or enlarged prostate if you have been prescribed tadalafil tablets for either of these reasons.

Before taking tadalafil

Some medicines are not suitable for people with certain conditions, and sometimes a medicine can only be used if extra care is taken. For these reasons, before you start taking tadalafil it is important that your doctor knows:

  • If you are pregnant, trying for a baby, or breastfeeding.
  • If you have any other heart problem or blood vessel condition.
  • If you have had an eye condition causing a loss of vision.
  • If you have problems with the way your liver works, or if you have problems with the way your kidneys work.
  • If you have recently had a heart attack.
  • If you have any disease, injury or deformity of your penis.
  • If you have sickle cell disease.
  • If you have ever had bone marrow cancer or leukaemia.
  • If you are taking or using any other medicines. This includes any medicines you are taking which are available to buy without a prescription, as well as herbal and complementary medicines, and recreational drugs.
  • If you have ever had an allergic reaction to a medicine.

How to take tadalafil

  • Before you take tadalafil, read the manufacturer’s printed information leaflet from inside your pack. It will give you more information about the tablets and will provide you with a full list of the side-effects which you could experience from taking them.
  • Take the tablets exactly as your doctor tells you to. The usual dose is two 20 mg tablets taken together, once daily.
  • Unless your doctor tells you otherwise, you can generally take tadalafil at a time of day that suits you. You should, however, try to take your doses at the same time of day, each day.
  • You can take tadalafil either with or without food. Swallow the tablets with a drink of water.
  • If you forget to take a dose, take it as soon as you remember as long as it is still within eight hours of the time you should have taken it. If when you remember, it is more than eight hours later, leave out the missed dose. Do not take two doses together to make up for a forgotten dose.

Getting the most from your treatment

  • It is recommended that you do not drink grapefruit juice with tadalafil. This is because there is a chemical in grapefruit juice which may increase the amount of tadalafil in your bloodstream. This could make side-effects more likely.
  • Try to keep your regular appointments with your doctor. This is so your doctor can check on your progress.
  • If you are due to have an operation or some other medical treatment, it is important that you tell the person carrying out the treatment that you are taking tadalafil.
  • Each time you collect a new supply of tablets from the pharmacy, make sure it looks to be the same as you have had before. If you are unsure, ask your pharmacist to check for you.
  • If you buy any medicines, check with a pharmacist that they are suitable to take with your other medicines.

Can tadalafil cause problems?

Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. The table below contains some of the more common ones associated with tadalafil. The best place to find a full list of the side-effects which can be associated with your medicine, is from the manufacturer’s printed information leaflet supplied with the medicine. Alternatively, you can find an example of a manufacturer’s information leaflet in the reference section below. Speak with your doctor or pharmacist if any of the following continue or become troublesome.

Very common tadalafil side-effects (these affect more than 1 in 10 people) What can I do if I experience this?
Headache, muscle aches and pains Ask your pharmacist to recommend a suitable painkiller. If the aches continue, let your doctor know
Facial flushing, nose or throat symptoms If troublesome, speak with your doctor for advice
Feeling sick (nausea) or being sick (vomiting), indigestion, tummy (abdominal) discomfort Stick to simple meals – avoid fatty or spicy foods
Common tadalafil side-effects (these affect fewer than 1 in 10 people) What can I do if I experience this?
Feeling faint or dizzy, blurred vision Do not drive and do not use tools or machines until your reactions/vision have returned to normal. If the problem with your eyesight starts suddenly, speak with your doctor
Nosebleeds, the feeling of having a ‘thumping heart’ (palpitations), increased menstrual bleeding If any become troublesome, speak with your doctor for advice

Important: if you experience any of the following, contact a doctor for medical attention straightaway:

  • An allergic-type reaction such as a rash or swelling around your face.
  • Chest pains
  • A sudden loss of vision or hearing
  • An erection lasting for more than four hours.

If you experience any other symptoms which you think may be due to the tablets, speak with your doctor or pharmacist for further advice.

How to store tadalafil

Important information about all medicines

Never take more than the prescribed dose. If you suspect that you or someone else might have taken an overdose of this medicine, go to the accident and emergency department of your local hospital. Take the container with you, even if it is empty.

This medicine is for you. Never give it to other people even if their condition appears to be the same as yours.

Do not keep out-of-date or unwanted medicines. Take them to your local pharmacy which will dispose of them for you.

Tadalafil – Uses, Side Effects, and More

Tadalafil 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.

How to use Tadalafil

Read the Patient Information Leaflet provided by your pharmacist before you start taking tadalafil 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 with or without food as directed by your doctor, usually once daily.

If you are using the liquid form of this medication, shake the bottle well for 30 seconds before each dose. Carefully measure the dose using a special measuring device/spoon. Do not use a household spoon because you may not get the correct dose.

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.

Side Effects

Dizziness, lightheadedness, headache, muscle pain, flushing, nausea, stuffy nose, or stomach upset may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.

To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Rarely, sudden decreased vision, including permanent blindness, in one or both eyes (NAION) may occur. If this serious problem occurs, stop taking tadalafil and get medical help right away. You have a slightly greater chance of developing NAION if you have heart disease, diabetes, high cholesterol, certain other eye problems (“crowded disk”), high blood pressure, if you are over 50, or if you smoke.

Rarely, a sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness, may occur. Stop taking tadalafil and get medical help right away if these effects occur.

Rarely, males may have a painful or prolonged erection lasting 4 or more hours. If this occurs, stop using this drug and get medical help right away, or permanent problems could occur.

Get medical help right away if you have any very serious side effects, including: increased shortness of breath or trouble breathing.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US – Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

Before taking tadalafil, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart problems (such as heart attack or life-threatening irregular heartbeat in the past 6 months, chest pain/angina, heart failure), stroke in the past 6 months, kidney disease, liver disease, high or low blood pressure, dehydration, penis conditions (such as angulation, fibrosis/scarring, Peyronie’s disease), history of painful/prolonged erection (priapism), conditions that may increase the risk of priapism (such as sickle cell anemia, leukemia, multiple myeloma), eye problems (such as retinitis pigmentosa, sudden decreased vision, NAION), bleeding disorders, active stomach ulcers, other lung conditions (such as pulmonary veno-occlusive disease).

This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

During pregnancy, tadalafil should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

A product that may interact with this drug is: riociguat.

Tadalafil can cause a serious drop in your blood pressure when used with nitrates, which can lead to dizziness, fainting, and rarely heart attack or stroke. Do not use any of the following with tadalafil or within 48 hours of your last dose of tadalafil: certain drugs used to treat chest pain/angina (nitrates such as nitroglycerin, isosorbide), recreational drugs called “poppers” containing amyl or butyl nitrite.

If you are also taking an alpha blocker medication (such as doxazosin, tamsulosin) to treat an enlarged prostate/BPH or high blood pressure, your blood pressure may get too low which can lead to dizziness or fainting. Your doctor may adjust your medications to minimize your risk of low blood pressure.

Other medications can affect the removal of tadalafil from your body, which may affect how tadalafil works. Examples include azole antifungals (such as itraconazole, ketoconazole), macrolide antibiotics (such as clarithromycin, erythromycin), HIV protease inhibitors (such as lopinavir), rifampin, ritonavir, among others.

Do not take this medication with any other product that contains tadalafil or other similar medications for erectile dysfunction-ED or pulmonary hypertension (such as sildenafil, vardenafil).

Tadalafil (Adcirca®)

Tadalafil is an oral medication called a phosphodiesterase-5 (PDE5) inhibitor approved for the treatment of pulmonary arterial hypertension (PAH) in World Health Organization (WHO) Group 1 patients. The goal of this therapy is to improve exercise ability and delay clinical worsening. Research studies showing the effectiveness of the medication included mostly patients with symptoms that were rated as WHO Functional Class II-III.

Tadalafil is marketed as Adcirca® for PAH and was approved by the United States Food and Drug Administration (FDA) in 2009. Tadalafil is also marketed as Cialis® for erectile dysfunction but not for the treatment of PAH.

How does tadalafil work?

PDE5 is a substance produced in the lungs and other parts of the body that breaks down another substance called cyclic guanosine monophosphate (GMP). Cyclic GMP causes the blood vessels (arteries) to relax and widen. Tadalafil decreases the activity of PDE5, so that more cyclic GMP is available for the blood vessels inside the lungs. This leads to relaxation, or widening, of those vessels. Relaxing and widening of the blood vessels in the lungs decreases the pulmonary blood pressure to the heart and improves its function. This reduces blood pressure in the lungs which generally results in the ability to be more active. Research studies have verified this improvement.

How is tadalafil given?

The recommended dose of tadalafil for the treatment of PAH is 40 mg (two 20 mg tablets) once daily with or without food. Your physician may have you begin with one tablet a day and then advance to the full dose of two tablets daily to allow you to adjust to the medication.

How is tadalafil supplied?

Adcirca™ is available as an orange, almond-shaped 20 mg pill.

How can a patient obtain tadalafil?

Tadalafil must be prescribed by a physician, and insurance approval must be obtained prior to starting therapy. It is carried by most retail and specialty pharmacies, including Accredo Health Inc., Aetna Specialty Pharmacy, AllianceRx Walgreens Prime, CVS Caremark, Cigna Tel-Drug, CuraScript, Kaiser Permanente Specialty Pharmacy, Precision Rx, and WellCare..

Will insurance pay for tadalafil?

It is expected that most health insurance plans will pay part of the cost of this medication. However, some plans still leave patients with a high out-of-pocket responsibility.

Depending on your insurance type, you may be eligible for assistance from the company that manufactures your therapy or from a non-profit charitable assistance organization. For more information visit www.PHAssociation.org/Help or call 301-565-3004.

What are the frequent side effects of tadalafil?

Tadalafil is generally well tolerated. The most frequent side effects are:

  • Headache
  • Muscle pain
  • Nasal stuffiness
  • Flushing of the skin
  • Respiratory infection
  • Leg or arm pain
  • Nausea
  • Back pain
  • Upset stomach

A reduction in blood pressure throughout the body may occur because tadalafil relaxes blood vessels (arteries) throughout the body. Caution must be used in patients with low blood pressure– for example, less than 90/50 mmHg. Caution is also needed in patients with dehydration, left-sided heart diseases and certain abnormalities of the body’s nervous system function.

Taking certain medications such as nitrates, nitric oxide donors or alpha blockers along with tadalafil can cause a significant drop in blood pressure. This could result in loss of consciousness or even death. You should make certain that you are not taking these medications before starting tadalafil. Use of tadalafil with medications known as nitrates is CONTRAINDICATED.

Prolonged erection (greater than four hours) in a male patient is a rare but very serious side effect; if this should happen to you, you should go to an emergency room or contact your doctor immediately.

Sudden loss of vision in one or both eyes has occurred in patients on PDE5 inhibitors. Such an event may represent serious dysfunction of the optic nerve and requires immediate medical attention.

Sudden loss of hearing may occur and may be accompanied by dizziness and/or ear ringing. Patients should seek prompt medical attention should this occur.

How are side effects of tadalafil monitored?

No regular bloodwork for side effects is required.

Your doctor may ask you to monitor your blood pressure on a regular basis particularly during your first few days on treatment or with a dose increase. Blood pressure monitoring is not needed for most patients.

If you experience any of the symptoms mentioned in the previous section, you should promptly notify your physician.

What are considerations for use of tadalafil in special populations?

The safety and effectiveness of tadalafil in pediatric PAH patients has not been established.

Tadalafil does not exhibit harm to the fetus in animal studies; however, it has not been studied in pregnant or nursing women. As there are no adequate and well-controlled human studies, tadalafil should be used in pregnancy only if clearly needed, and caution should be exercised in nursing women.

There is limited experience using tadalafil in patients with liver disease. In mild or moderate liver disease (Child Pugh Class A or B), one should consider starting tadalafil at a dose of 20 mg once daily. In severe liver disease (Child Pugh Class C), it is generally recommended to avoid use.

In patients with mild-to-moderate kidney disease (creatinine clearance 31 to 80 ml/min), it is recommended to start tadalafil at 20 mg once daily and to increase to 40 mg once daily based on individual tolerability. In patients with severe kidney disease (creatinine clearance < 30 ml/min or on dialysis), it is recommended to avoid use of tadalafil. This is because severe kidney disease increases the amount of tadalafil in the bloodstream, even in patients on dialysis. Also, there is limited experience using tadalafil in these patients.

Tadalafil is not recommended in patients with either of two rare diseases often associated with PAH: pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.

Could a patient be allergic to tadalafil?

What are important drug interactions with tadalafil? (Please see package insert for full details)

Tadalafil should not be used in combination with nitrates or nitric oxide donors as an unsafe drop in systemic blood pressure may occur.

Caution should be used if tadalafil is to be used in combination with either alcohol or anti-hypertensive medications. Tadalafil is broken down predominantly by an enzyme called CYP3A in the liver; therefore, important interactions may occur with medications that affect this enzyme pathway. Simultaneous use of bosentan and tadalafil may result in decreased tadalafil blood levels. However, changes in the usual dosing of these two medications when used in combination are not typically necessary.

Patients with human immunodeficiency virus (HIV or AIDS), who are taking medicines called antiretroviral agents, should not use a phosphodiesterase inhibitor such as tadalafil since it can dramatically impair the efficacy of the antiretroviral.

Miscellaneous considerations:

Is there any risk of blindness when using tadalafil?

There have been rare reports of blindness with use of all the currently available PDE5 inhibitors, including tadalafil. This type of blindness, which may be permanent, is called non-arteritic anterior ischemic optic neuropathy (NAION). It is not yet clear whether this is related to the use of tadalafil or to the underlying cardiovascular diseases that place the persons at risk for this particular type of blindness, even in the absence of tadalafil use.

There is no research to determine whether use of tadalafil is beneficial or safe in patients with retinitis pigmentosa, and use in these patients is not recommended.

As noted above, patients taking tadalafil should seek immediate medical attention in the event of sudden vision loss.

Can men and women take tadalafil?

Yes, studies have evaluated tadalafil in both men and women with PAH, and no differences in side effects have been reported. Studies have not shown any effect on sexual function in women who have taken tadalafil.

Clinical utility of tadalafil in the treatment of pulmonary arterial hypertension: an evidence-based review

The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Abstract

Pulmonary arterial hypertension (PAH) is a chronic and disabling condition characterized by an elevated pulmonary vascular resistance and an elevated mean pulmonary arterial pressure. Despite recent improvements in treatment availability, PAH remains challenging to treat, burdensome for patients, and ultimately incurable. Tadalafil is a phos-phodiesterase-5 inhibitor that is administered once daily by mouth for the treatment of PAH. Current treatment guidelines recommend tadalafil as an option for patients with World Health Organization functional class II or III PAH. In a placebo-controlled clinical trial, patients taking tadalafil demonstrated significantly improved exercise capacity as measured by the 6-minute walk distance. Patients also experienced decreased incidence of clinical worsening, increased quality of life, and improved cardiopulmonary hemodynamics. Uncontrolled studies and smaller trials have indicated a possible role for tadalafil as a suitable alternative to sildenafil and as a beneficial add-on option when used in combination with other treatments for PAH. Tadalafil is generally safe and well tolerated. Adverse events are typically mild-to-moderate in intensity, and discontinuation rates are usually low. The purpose of this review is to provide an evidence-based evaluation of the clinical utility of tadalafil in the treatment of PAH.

Outcome measure Evidence Implications
Disease-oriented evidence Clinical trials Tadalafil has consistently demonstrated efficacy in improving exercise capacity when used as monotherapy. Tadalafil may also increase time to clinical worsening and improve cardiopulmonary hemodynamics when used as monotherapy. Strong evidence from large controlled trials supporting additional benefit of using tadalafil in combination therapy is lacking.
Patient-oriented evidence Clinical trials Tadalafil has demonstrated efficacy in improving patient quality of life when used as monotherapy. Tadalafil is generally safe and well tolerated.
Economic evidence None available None available

Introduction

Pulmonary arterial hypertension (PAH) is a rare, however, debilitating chronic condition that remains progressive and incurable despite recent approval of several novel treatment options. In PAH, blood flow through the lungs is impaired, resulting in increased pulmonary vascular resistance (PVR) and an elevated mean pulmonary arterial pressure (mPAP). These factors often lead to pulmonary vasculature fibrosis and eventual right ventricular heart failure.1 Pulmonary hypertension is classified by the World Health Organization (WHO) into five groups based on a diversity of etiologies, including group 1: PAH, which is idiopathic, heritable, drug/toxin induced, or associated with connective tissue disease, portal hypertension, HIV infection, or congenital heart disease; group 2: pulmonary hypertension due to left heart disease; group 3: pulmonary hypertension due to lung disease; group 4: chronic thromboembolic pulmonary hypertension; and group 5: pulmonary hypertension with unclear multifactorial mechanisms.2

Patients with PAH commonly present with dyspnea on exertion; however, additional symptoms, including fatigue, weakness, angina, syncope, palpitations, and lower extremity edema, may also be present.3 The severity of PAH is based upon patient symptoms and activity level and is categorized by the WHO functional classification scheme which is as follows: WHO Class I patients have no limitation in physical activity and do not experience symptoms (dyspnea, fatigue, chest pain, or near syncope) with ordinary physical activity; WHO Class II patients have a slight limitation in physical activity experiencing symptoms with ordinary physical activity; WHO Class III patients have a marked limitation in physical activity experiencing symptoms with less than ordinary activity; and WHO Class IV patients are unable to carry out any physical activity without symptoms and experience symptoms at rest or with very slight activity.4 The 6-minute walk distance (6MWD) and the Borg dyspnea scale are often employed by clinicians and researchers to quantify a patient’s exercise capacity and breathing difficulty as well as to gage response to treatment. Cardiopulmonary hemodynamics, including PVR, mPAP, pulmonary arterial wedge pressure, and cardiac index (CI), are also obtained and assessed throughout the disease diagnostic and monitoring process.5

PAH is associated with poor survival, increased morbidity, and diminished quality of life (QoL).6,7 Patients often require a multidisciplinary approach to treatment in which needs relating to physical care as well as emotional and social care can be met.7,8 Currently, a number of guidelines exist to aid clinicians in treating patients with PAH.3,4,7,9 Although the available guidelines vary slightly in content, they generally agree in treatment approach. Goals of the treatment include improvement of symptoms, QoL, and survival.3 Patients who have less severe disease and who respond during acute vasoreactivity testing are initially started on a trial therapy with an oral calcium channel blocker (CCB). Patients who either fail to respond during acute vasoreactivity testing, fail to maintain a response while taking an oral CCB, or present with more severe diseases are considered for treatment with other approved options. Prostacyclin analogs (epoprostenol, iloprost, treprostinil), endothelin receptor antagonists (ERAs; ambrisentan, bosentan, macitentan), phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil), and a soluble guanylate cyclase (sGC) stimulator (riociguat) are all currently available for the treatment of PAH ( Table 1 ). Oral agents, such as ERAs, PDE-5 inhibitors, treprostinil, and riociguat, are recommended for patients with WHO functional class II. Patients with WHO functional class III are treated with either an oral medication or a prostacyclin analog (inhaled or parenteral). Patients at higher risk, WHO functional class IV, should be treated with intravenous epoprostenol.9 Variations from this approach as well as treatment after inadequate clinical response to initial therapy can include strategies such as combination therapy and are preferentially implemented at expert PAH care centers according to the clinician’s judgment.4 Adjunctive therapies, including diuretics, anticoagulants, digoxin, or supplemental oxygen, may also be employed to better achieve treatment goals.

Table 1

Treatment options for pulmonary arterial hypertension

Treatment option Route of administration Dosing frequency (doses/day) Restricted dispensing Relative cost *
Calcium channel blockers Oral Various No $
Prostacyclin analogs
Epoprostenol Intravenous Continuous No $$
Iloprost Inhaled 6–9 No $$$
Treprostinil Intravenous/subcutaneous Continuous No $$$
Inhaled 4 No $$
Oral 2–3 No $$
Endothelin receptor
Antagonists
Ambrisentan Oral 1 Yes $$$
Bosentan Oral 2 Yes $$$
Macitentan Oral 1 Yes $$$
Phosphodiesterase-5 inhibitors
Sildenafil Oral 3 No $$
Tadalafil Oral 1 No $$
Soluble guanylate cyclase
Stimulator
Riociguat Oral 3 Yes $$$

* According to average wholesale price in 2015 US dollars for a 75 kg patient. $, cost/year $50,000. Data used with permission from Lexicomp Online ® , Lexi-Drugs ® , Hudson, Ohio: Lexi-Comp, Inc.; April 1, 2015.10

Although the causal mechanisms for the pathogenesis of PAH remain unclear, the progression of PAH is the result of pulmonary arterial endothelial dysfunction leading to an imbalance between key pulmonary vascular mediators, such as decreased nitric oxide (NO) and prostracylin and increased endothelin-1.11,12 This imbalance leads to increased thrombosis, vasoconstriction, and proliferation of smooth muscle and endothelial cells within the pulmonary vasculature.12 Current treatments are directed at correcting the imbalance in these mediators.

While the body of evidence supporting PAH treatment is continually growing, there remain several important limitations to current treatment recommendations.13 PAH has many etiologies, including some which remain grouped as idiopathic. Studies have used a broad definition of PAH in patient recruitment resulting in efficacy data from a heterogeneous selection of etiologies. As such, there are limitations in knowledge about specific treatment efficacy in each form of PAH.4 Furthermore, a few studies have evaluated the relative utility of available treatment options in head-to-head comparisons. This has resulted in a paucity of data supporting the use of a specific agent as first-line treatment.9,14 In addition to limitations in treatment recommendations, currently available treatment options can be at times challenging and burdensome to use. With the exception of CCBs, there are no means to effectively predict benefit from the available treatment options.4 Treatment options can be overly burdensome to patients as a result of high cost, frequent dosing, and inconvenient administration. Several agents are contraindicated in pregnancy and possess clinically important drug interactions.4,9 These limitations and others drive in part the need for novel treatment options. The purpose of this review is to provide an evidence-based evaluation of the clinical utility of tadalafil in the treatment of PAH.

Tadalafil

As mentioned previously, NO production and release is decreased as a result of endothelial dysfunction.15 NO causes vasodilation of the pulmonary vasculature by increasing the production of the second messenger cyclic guanosine monophosphate (cGMP) via activation of sGC ( Figure 1 ).16 cGMP activates protein kinase G, which in turn activates sarcolemmal potassium channels. This results in intracellular hyperpolarization and inhibition of voltage-gated calcium channels ultimately leading to vasorelaxation.17 Thus, the decrease in NO availability seen in PAH results in decreased cGMP and increased pulmonary arterial vasoconstriction. PDE-5 is the predominant phosphodiesterase in the pulmonary vasculature and is responsible for the rapid degradation and inactivation of cGMP.18,19 Treatment with PDE-5 inhibitors (sildenafil or tadalafil) results in a competitive inhibition of cGMP degradation resulting in increased cGMP concentrations.20 The increased cGMP concentrations lead to relaxation of pulmonary vascular smooth muscle and vasodilation of the pulmonary vascular bed.16 Currently, sildenafil (Revatio ® ) and tadalafil (Adcirca ® ) are the only PDE-5 inhibitors approved by the United States Food and Drug Administration for the treatment of WHO group 1 PAH.21,22 Other PDE-5 inhibitors, such as vardenafil, have not been approved for the treatment of PAH, and the limited evidence available using these drugs in the treatment of PAH prohibit meaningful comparison to tadalafil. Several pharmacokinetic and pharmacodynamic differences exist between sildenafil and tadalafil ( Table 2 ). One of the main pharmacokinetic differences is the long plasma half-life (t1/2) of 17.5 hours with tadalafil, which facilitates once-daily dosing as compared to the required three times daily dosing of sildenafil.22,23 When compared to sildenafil, the less frequent dosing of tadalafil is advantageous in terms of patient convenience and adherence.24 Tadalafil is primarily metabolized by the cytochrome P450 3A (CYP3A) enzyme subfamily to an inactive metabolite. As such, concomitant administration with medications that induce or inhibit CYP3A may result in significant drug–drug interactions.21,25 Bosentan, an ERA used in the treatment of PAH, induces CYP3A4 and has been demonstrated to decrease tadalafil serum concentrations and exposure.25 Although tadalafil is not primarily eliminated renally, starting doses of tadalafil require adjustment in patients with a creatinine clearance (CrCl) of 31–80 mL/min, and tadalafil should be avoided in patients with a CrCl

The role of phosphodiesterase-5 (PDE-5) in the intracellular signaling pathway of the pulmonary vasculature.

Notes: NO and NPs bind to soluble and particulate guanylate cyclase, respectively, causing enzymatic activation and conversion of GTP to cGMP. Through the activation of protein kinase G, cGMP serves as a second messenger leading to cellular response resulting in pulmonary artery vasodilation. cGMP degradation to GMP by PDE-5 limits this cellular response. Thus, inhibition of PDE-5 by tadalafil results in an enhanced cellular response to vasodilative ligands. Data from Moncada and Higgs,16 and Archer et al.17

Abbreviations: NO, nitric oxide; NPs, natriuretic peptides; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; PDE-5, phosphodiesterase-5.

Table 2

Phosphodiesterase-5 inhibitors used for the treatment of pulmonary hypertension

Agent Tmax Hepatic metabolism Half-life Dose Renal dose
Sildenafil (Revatio)22 60 minutes CYP3A (major), CYP2C9 (minor) 4 hours 20 mg 3 times a day approximately 4–6 hours apart None required
Tadalafil (Adcirca)21 75–90 minutes CYP3A 17.5 hours 40 mg (2×20 mg) once daily CrCl 31–80 mL/min: 20 mg once daily; avoid in severe renal impairment (CrCl

Abbreviations: Tmax, time to maximal effect; CYP, cytochrome P450; CrCl, creatinine clearance.

The pharmacodynamic differences between sildenafil and tadalafil are based on each agent’s selectivity for various PDE isozymes.26 Tadalafil is >1,000-fold more selective for PDE-5 than for PDE-1–4 and PDE-7–10, 780-fold more selective for PDE-5 than for PDE-6, and only seven-fold more selective for PDE-5 than for PDE-11. In comparison, sildenafil is 41-fold more selective for PDE-5 than for PDE-1, seven-fold more selective for PDE-5 than for PDE-6, and 203-fold more selective for PDE-5 than for PDE-11. These differences in selectivity may result in the differences in adverse effects dependent on the isozyme location and activity. PDE-6 is expressed only in the retina and is important for visual transduction. Inhibition of PDE-6 can result in visual disturbances, which have been more frequently reported with sildenafil than with tadalafil. PDE-1 is expressed in the brain, myocardial cells, and vascular smooth muscle cells. Inhibition of PDE-1 may cause vasodilatation, flushing, and tachycardia. PDE-11 is expressed in the liver, kidney, skeletal muscle, prostate, and testes. Tadalafil is less selective for PDE-11 than sildenafil and is more likely to be associated with back pain and myalgias than with sildenafil.

Tadalafil, as well as other PDE-5 inhibitors, has several pharmacodynamic drug–drug interactions of concern. Tadalafil does not significantly lower systemic blood pressure; however, concomitant administration of tadalafil with medications that do lower systemic blood pressure can result in potentiation of hypotension. Coadministration of tadalafil with nitrates is contraindicated due to the risk of significant hypotension, and, because of the long t1/2 of tadalafil, nitrates should not be administered for 48 hours following tadalafil administration.21 Caution is warranted when tadalafil is used in combination with certain antihypertensives such as alpha-adrenergic blocking agents (eg, doxazosin).21 PDE-5 inhibitors, including tadalafil, are contraindicated with riociguat, a recently approved agent for the treatment of PAH.27 Riociguat is a sGC stimulator that results in increased production of cGMP and resultant arterial vasodilation ( Figure 1 ). Because PDE-5 inhibitors decrease degradation of cGMP, there is a risk of profound hypotension if administered concomitantly with riociguat. Though not documented, it would be expected that coadministration of tadalafil with prostacyclin analogs would increase the risk of hypotension and should be used with caution.

As of 2015, a monthly supply of Adcirca 40 mg once daily is estimated to cost about US$2,700. While there is currently no economic evidence comparing tadalafil to other PAH treatment options, several analyses have demonstrated a favorable cost-effective profile for sildenafil when compared to other PAH treatment options.28,29 Tadalafil may also be a cost-effective option; however, further research is needed to provide insight into tadalafil’s comparative cost-effectiveness. PAH treatment guidelines recommend using tadalafil in patients who are WHO functional class II or III.3,4,7,9 In recent years, a number of studies have provided insight into the clinical efficacy and effectiveness of tadalafil in the treatment of PAH ( Table 3 ).24,30–41

Table 3

Chronological summary of studies demonstrating tadalafil clinical efficacy

Tadalafil use Author (year) n * Study design WHO-FC Outcome Significant tadalafil findings
Monotherapy Ghofrani et al (2004)30 25 R, prospective study II–IV Change in PVRI from baseline to one dose ↓ PVRI
Aggarwal et al (2007)31 13 Prospective, open-label study II–IV Treadmill exercise capacity and pulmonary hemodynamics from baseline to week four ↑ treadmill time
No change in mPAP and PVR Improved functional class
Bharani et al (2007)32 8 R, DB, PLC, crossover study II–III Exercise capacity from baseline to week four ↑ 6MWD
↓ PASP
↓ Borg dyspnea score
Galiè et al (2009),33PHIRST-1 study 405 R, DB, MC, PLC trial I–IV Exercise capacity from baseline to week 16 ↑ 6MWD
↓ mPAP, ↓ PVR, and ↑ CI
↑ Time to clinical worsening and
↓ incidence of clinical worsening
↑ QoL
No improvements in Borg dyspnea score and WHO-FC
Takatsuki et al (2012)34 33 Retrospective study I–IV Pulmonary hemodynamics after transition from sildenafil in pediatric patients ↓mPAP, PVR and PVR/SVR
No change in CI and 6MWD
31/33 successfully transitioned
Shlobin et al (2012)35 35 Retrospective study NR Clinical stability after transition from sildenafil 30/35 successfully transitioned
Oudiz et al (2012),36 PHIRST-2 study 357 DB, MC, uncontrolled extension study I–IV Exercise capacity from baseline and week 16 for an additional 52 weeks after completing the PHIRST-1 study Maintenance of an ↑ 6MWD
↑ 6MWD in previously unimproved patients
Acceptable long-term safety profile
Sabri and Beheshitan (2013)37 18 Prospective, uncontrolled study I–III Clinical stability after transition from sildenafil ↑ 6MWD
↑ blood oxygen saturation
15/18 successfully transitioned
Shapiro et al (2013)38 98 Retrospective study NR Clinical stability after transition from sildenafil No change in 6MWD
No change in BNP levels
95/98 successfully transitioned
Frantz et al (2014)24 35 MC, prospective, uncontrolled study I–III Treatment satisfaction after transition from sildenafil ↑ convenience TSQM scores, but no change in global TSQM scores
No change in 6MWD
30/35 successfully transitioned
Lichtblau et al(2015)39 13 Retrospective study II–IV Clinical feasibility of transition from sildenafil after experiencing intolerable side effects 6/13 successfully transitioned
Combination therapy Caojin et al (2014)40 47 Prospective, open-label study I–IV Clinical benefit from baseline to 6 months after addition of tadalafil to inhaled iloprost ↑ 6MWD
↓ PVR and ↑ systemic oxygen saturation
↓ Borg dyspnea score
Improved WHO-FC
Zhuang et al (2014)41 124 R, DB, PLC study II–IV Exercise capacity from baseline to week 16 after addition of tadalafil to stable ambrisentan therapy ↑ 6MWD
No change in mPAP, PVR, and CO
↓ incidence of clinical worsening
No improvement in WHO-FC

* Reported are sample sizes used during the analysis that generated tadalafil key findings. ↑, increased. ↓, decreased.

Abbreviations: PVRI, pulmonary vascular resistance index; mPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance; R, randomized; DB, double-blind; PLC, placebo-controlled; 6MWD, 6-minute walk distance; PASP, pulmonary artery systolic pressure; MC, multicenter; CI, cardiac index; QoL, quality of life; WHO-FC, World Health Organization functional class; SVR, systemic vascular resistance; NR, not reported; PHIRST, Pulmonary Arterial Hypertension and Response to Tadalafil; BNP, brain natriuretic peptide; TSQM, treatment satisfaction questionnaire for medication; CO, cardiac output.

Clinical efficacy

Monotherapy

The earliest available literature providing evidence for the clinical utility of tadalafil in treating PAH came from case studies, as well as small prospective studies. From 2004 to 2008, a number of case studies were published that detailed the successful use of tadalafil in a total of 17 patients. From these various case reports, it is evident that tadalafil showed potential in providing PAH patients with improved exercise capacity.42–46 In 2004, a small prospective study gave insight into tadalafil’s potential to alter cardiopulmonary hemodynamics by demonstrating that one dose of tadalafil affected cardiopulmonary hemodynamics in a manner similar to that of sildenafil.30

In 2009, results from Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST)-1 Phase III clinical trial were published.33 The PHIRST-1 was a randomized, double-blind, multicenter, placebo-controlled, dose-ranging trial in 405 PAH patients with disease that was idiopathic or heritable in nature or related to anorexigen use, connective tissue disease, HIV infection, or congenital shunts. Patients were randomized to take placebo, tadalafil 2.5 mg, tadalafil 10 mg, tadalafil 20 mg, or tadalafil 40 mg once daily for 16 weeks. Patients who were receiving treatment with prostacyclin therapy were excluded; however, patients on stable treatment with bosentan could participate in the study. The primary endpoint was the change from baseline to week 16 in 6MWD. Secondary endpoints included changes in WHO functional class, time from randomization to clinical worsening, Borg dyspnea score, QoL, cardiopulmonary hemodynamics, and safety. The 6MWD, Borg dyspnea score, and WHO functional class were measured every 4 weeks during the study. Tadalafil doses of 10 mg, 20 mg, and 40 mg significantly improved the mean placebo-corrected 6MWD by 20 m (P=0.047), 27 m (P=0.028), and 33 m (P<0.001), respectively, at week 16. No significant changes were seen in WHO functional class or Borg dyspnea scores. Time to clinical worsening was significantly increased (P=0.041), and incidence of clinical worsening significantly decreased (P=0.038) only in the tadalafil 40 mg group when compared to placebo. Significant improvements in QoL as measured using validated questionnaires were also seen in patients taking tadalafil 40 mg.47 Cardiopulmonary hemodynamics, including mPAP and PVR, were significantly decreased in the 93 patients for whom data were available while taking tadalafil doses of 20 mg and 40 mg. A significant improvement in CI was also seen in patients taking tadalafil 40 mg.

The patients who had completed PHIRST-1 and the patients who had discontinued PHIRST-1 while taking placebo were eligible for continued participation in a double-blind, 52-week, uncontrolled extension study known as the PHIRST-2 study.36 Durability of efficacy and long-term safety were evaluated in the 357 patients who participated. If the patients were stable on tadalafil 20 mg from the PHIRST-1 study, they continued this treatment for 52 weeks. All the other patients received tadalafil 40 mg daily for 52 weeks. Durability of efficacy was assessed by comparing 6MWD across the PHIRST-1 and PHIRST-2 studies. WHO functional class and factors associated with clinical worsening were also assessed in patients who had received treatment with tadalafil 20 mg or tadalafil 40 mg in PHIRST-1. Improvements in 6MWD that were observed at the end of the PHIRST-1 study were maintained at week 52. In patients who had completed the PHIRST-1 study with placebo, tadalafil 2.5 mg, or tadala-fil 10 mg, 6MWD improved at the end of week 52; however, the 6MWD did not improve to a level similar to that seen at the conclusion of PHIRST-1 in patients taking tadalafil doses of 20 mg or 40 mg. Multivariate analysis identified race, PAH etiology, duration of bosentan use, age, baseline WHO functional class, and 6MWD at PHIRST-1 baseline as the risk factors for clinical worsening.

In recent years, several uncontrolled prospective and retrospective studies evaluating the use of tadalafil after transitioning from sildenafil have been published.24,34,35,37–39 These studies reported data from patients taking a final dose of sildenafil in the evening, and then starting tadalafil the next day. A successful transition from sildenafil to tadalafil was obtained in a combined total of 207 out of 232 patients. Generally, these studies showed that there was no change in 6MWD after transitioning. One study prospectively evaluated patient satisfaction after transitioning as measured by the Treatment Satisfaction Questionnaire for Medication (TSQM). Scores relating to convenience after transitioning were increased; however, global TSQM scores did not change.24 Other studies demonstrated the clinical feasibility of transitioning to tadalafil in unique samples involving pediatric patients as well as in patients who had previously experienced intolerable side effects while taking sildenafil.34,39

In summary, the majority of evidence supporting the efficacy of tadalafil in PAH treatment comes from a large randomized clinical trial, the associated 52-week extension study which followed as well as from post hoc analyses of that clinical trial. In total, these studies provide strong evidence that tadalafil 40 mg significantly improves 6MWD for a sustained period of time. Additionally, tadalafil 40 mg improves cardiopulmonary hemodynamics, time to clinical worsening, and QoL.33,36,48,49 Several uncontrolled studies have provided some evidence supporting the effectiveness of switching from sildenafil to tadalafil.24,34,35,37–39

Combination therapy

Evidence for the use of tadalafil in combination with other PAH treatments was initially furnished by pharmacokinetic studies as well as case reports. In 2008, Wrishko et al showed that coadministration of tadalafil with bosentan, a P450 inducer, for 10 days in 14 healthy subjects decreased tadalafil exposure as measured by area under the curve (AUC) by 41.5% as well as decreased the maximum plasma concentration (Cmax) by 26.6%.25 Conversely, coadministration of tadalafil with ambrisentan in 23 healthy subjects did not result in decreased tadalafil plasma concentrations, including AUC or Cmax.50 Tadalafil pharmacokinetics were prospectively evaluated in 23 pediatric patients, 16 of whom were also taking bosentan. Along with age and estimated glomerular filtration rate, concomitant bosentan use was not found to have an effect on oral clearance (CL/F).51 From 2008 to 2011, four case studies detailed the successful and effective use of tadalafil in combination with a prostacyclin (n=4), sitaxentan (n=6), or a combination of bosentan and beraprost (n=1).52–55

In 2014, results were published from two prospective studies from the People’s Republic of China examining the efficacy of tadalafil when used in various combinations with other PAH treatments.40,41 The first study was a prospective, uncontrolled, open-label evaluation of 47 patients with PAH secondary to congenital heart disease.40 Patients received a low dose of iloprost administered as 2.5 µg inhaled six times a day for 6 months and then were started on tadalafil 5 mg once daily in combination with iloprost for an additional 6 months. Outcome measures included change in 6MWD, Borg dyspnea score, oxygen saturation, WHO functional class, and cardiopulmonary from baseline to 6 months of monotherapy with iloprost. These same measures were assessed again after an additional 6 months in order to compare results of iloprost monotherapy with combination therapy. Iloprost monotherapy resulted in significant improvements in 6MWD, Borg dyspnea score, oxygen saturation, and WHO functional class. Following 6 months of combination therapy, there were additional significant improvements in these same measures when compared to values obtained at the end of 6 months of monotherapy. The 6MWD significantly increased from a mean of 457.22 m after monotherapy to a mean of 490.09 m (P<0.05) after combination therapy. Additionally, WHO functional class, Borg dyspnea scores, and measures of cardiopulmonary hemodynamics, including PVR, decreased significantly, while systemic oxygen saturation during exercise increased significantly.

The second study conducted exclusively in the People’s Republic of China was a randomized, double-blind, placebo-controlled study evaluating the benefits of adding tadalafil in 124 stable patients who had previously received ambrisentan 10 mg daily for 4 months.41 The study included patients with idiopathic or heritable PAH or with PAH related to anorexigen use, connective tissue disease, or repaired congenital heart disease. Patients were randomized to either placebo or tadalafil 40 mg daily for 16 weeks in addition to ambrisentan. Outcome measures included change in 6MWD, WHO functional class, incidence of clinical worsening, and cardiopulmonary hemodynamics assessed every 4 weeks from baseline to week 16. The 6MWD was found to be significantly increased from baseline at weeks 8, 12, and 16 in patients receiving tadalafil combination, whereas the 6MWD was not found to be significantly increased from baseline at any week in patients receiving placebo. When compared between groups at week 16, 6MWD was found to be significantly greater by 36.1 m (P=0.042) in patients receiving tadalafil combination compared to patients receiving placebo combination. By week 16, there were nine fewer incidences of clinical worsening in the tadalafil treatment group (P=0.046); however, there were no significant improvements in WHO functional class or cardiopulmonary hemodynamics.

In summary, subgroup analysis of the PHIRST-1 study indicates that there may be some additional benefit in using tadalafil in combination with bosentan; however, results from this analysis failed to be statistically significant and conclusions were based on small sample sizes.56 Some evidence is available supporting tadalafil use in combination with iloprost.40 Finally, as demonstrated by one randomized study, tadalafil may provide additional benefit when used in combination with ambrisentan in increasing 6MWD and decreasing incidence of clinical worsening.41 As opposed to bosentan, ambrisentan does not induce CYP3A and would not be expected to decrease tadalafil serum concentrations nor therapeutic efficacy. Strong evidence for tadalafil use in combination therapy is lacking, and larger controlled studies will need to be performed in order to better understand what role, if any, tadalafil has when used in combination with PAH therapies.

Safety and tolerability

Tadalafil is considered to be safe and typically well tolerated when taken for the treatment of PAH. The most common adverse event (AE) associated with tadalafil use is headache.21 Approximately 15%, 32%, and 42% of patients during the PHIRST-1 study experienced headache while taking placebo, tadalafil 20 mg, and tadalafil 40 mg, respectively. These values dropped to 14% and 16% during the 52-week PHIRST-2 extension study for tadalafil 20 mg and tadalafil 40 mg, respectively. Other AEs, including myalgias and flushing, were reported at a lesser frequency than headache and were typically mild-to-moderate in intensity. Discontinuation rates during the PHIRST-1 study were ∼16% and were similar in all treatment groups. Discontinuation rates after 52 weeks of therapy remained similar to those seen during the PHIRST-1 study.33,36 Furthermore, discontinuation rates in elderly patients did not appear to differ from those observed in younger patients.48 When tadalafil was used as an alternative after transitioning from sildenafil, tolerability of tadalafil was reported in the majority of patients.24,34,35,37–39 Additionally, one study reported that about half of the patients who had experienced intolerable AEs while taking sildenafil were able to tolerate and successfully transition to tadalafil.39 Although data are limited, incidence of AEs appears to be similar in pediatric population.34

Studies evaluating tadalafil safety when used in combination with other PAH treatment options did not report a significantly increased incidence of AEs for tadalafil combination use with bosentan, ambrisentan, and inhaled iloprost. Discontinuation rates also remained similar to those rates observed in patients on tadalafil monotherapy.40,41,56 In addition to mild-to-moderate AEs, rare but serious AEs associated with tadalafil may occur, including vision loss, hearing loss, and priapism.21

Conclusion

Tadalafil is a convenient and generally well tolerated once-a-day PDE-5 inhibitor for treating patients with PAH. There is strong evidence that tadalafil at doses of 40 mg daily improves exercise capacity for sustained periods of time when used as monotherapy with WHO group 1 PAH patients with WHO functional class II or III symptoms. Tadalafil may also be beneficial at improving cardiopulmonary hemodynamics, QoL, and time to clinical worsening. Data from uncontrolled studies indicate that tadalafil may be a suitable alternative to sildenafil for patients desiring decreased pill burden. While the role for tadalafil in combination therapy appears promising, evidence-based recommendations for tadalafil use in combination therapy are currently difficult given the lack of evidence from large controlled trials.

Footnotes

The authors report no conflicts of interest in this work.

References

1. Chin KM, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol. 2008; 51 (16):1527–1538. [PubMed] [Google Scholar]

2. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013; 62 (25):D34–D41. [PubMed] [Google Scholar]

3. McLaughlin VV, Archer SL, Badesch DB, et al.American College of Cardiology Foundation Task Force on Expert Consensus Documents, American Heart Association, American College of Chest Physicians, American Thoracic Society, Inc, Pulmonary Hypertension Association ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009; 53 (17):1573–1619. [PubMed] [Google Scholar]

4. Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest. 2014; 146 (2):449–475. [PMC free article] [PubMed] [Google Scholar]

5. Badesch DB, Champion HC, Gomez-Sanchez MA. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54 (Suppl 1):S55–S66. [PubMed] [Google Scholar]

6. D’Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991; 115 (5):343–349. [PubMed] [Google Scholar]

7. Galie N, Hoeper MM, Humbert M, et al.ESC Committee for Practice Guidelines (CPG) Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT) Eur Heart J. 2009; 30 (20):2493–2537. [PubMed] [Google Scholar]

8. Howard LS, Ferrari P, Mehta S. Physicians’ and patients’ expectations of therapies for pulmonary arterial hypertension: where do they meet? Eur Respir Rev. 2014; 23 (134):458–468. [PMC free article] [PubMed] [Google Scholar]

9. Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62 (Suppl D):D60–D72. [PubMed] [Google Scholar]

10. Lexicomp Online® [database on the Internet] Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc; Apr 1, 2015. [Accessed October 9, 2015]. Available from: http://online.lexi.com/crlsql/servlet/crlonline. [Google Scholar]

11. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation. 2004; 109 :159–165. [PubMed] [Google Scholar]

12. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004; 351 :1655–1665. [PubMed] [Google Scholar]

13. Hemnes AR. Pulmonary arterial hypertension treatment guidelines: new answers and even more questions. Chest. 2014; 146 (2):239–241. [PMC free article] [PubMed] [Google Scholar]

14. Tonelli AR, Zein J, Ioannidis JP. Geometry of the randomized evidence for treatments of pulmonary hypertension. Cardiovasc Ther. 2013; 31 (6):e138–e146. [PMC free article] [PubMed] [Google Scholar]

15. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995; 333 :214–221. [PubMed] [Google Scholar]

16. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993; 329 :2002–2012. [PubMed] [Google Scholar]

17. Archer SL, Huang JM, Hampl V, Nelson DP, Shultz PJ, Weir EK. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1994; 91 :7583–7587. [PMC free article] [PubMed] [Google Scholar]

18. Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev. 1995; 75 :725–748. [PubMed] [Google Scholar]

19. Corbin JD, Beasley A, Blount MA, Francis SH. High lung PDE5: a strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun. 2005; 334 :930–938. [PubMed] [Google Scholar]

20. Francis SH, Corbin JD. Molecular mechanisms and pharmacokinetics of phosphodiesterase-5 antagonists. Curr Urol Rep. 2003; 4 :457–465. [PubMed] [Google Scholar]

21. Adcirca® (tadalafil) tablets for oral administration [package insert] Indianapolis, IN: Eli Lily and Company; 2014. [Google Scholar]

22. Revatio® (sildenafil) tablets, for oral use [package insert] New York, NY: Pfizer Labs; 2012. [Google Scholar]

23. Forgue ST, Patterson BE, Bedding AW, et al. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2006; 61 :280–288. [PMC free article] [PubMed] [Google Scholar]

24. Frantz RP, Durst L, Burger CD, et al. Conversion from sildenafil to tadalafil: results from the sildenafil to tadalafil in pulmonary arterial hypertension (SITAR) study. J Cardiovasc Pharmacol Ther. 2014; 19 (6):550–557. [PubMed] [Google Scholar]

25. Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol. 2008; 48 (5):610–618. [PubMed] [Google Scholar]

26. Bischoff E. Potency, selectivity, and consequences of nonselectivity of PDE inhibition. Int J Impot Res. 2004; 16 (Suppl 1):S11–S14. [PubMed] [Google Scholar]

27. Adempas® (riociguat) tablets, for oral use [package insert] Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2014. [Google Scholar]

28. Garin MC, Clark L, Chumney EC, Simpson KN, Highland KB. Cost-utility of treatments for pulmonary arterial hypertension: Markov state-transition decision analysis model. Clin Drug Investig. 2009; 29 (10):635–646. [PubMed] [Google Scholar]

29. Chen YF, Jowett S, Barton P, et al. Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation. Health Technol Assess. 2009; 13 (49):1–320. [PubMed] [Google Scholar]

30. Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2004; 44 (7):1488–1496. [PubMed] [Google Scholar]

31. Aggarwal P, Patial RK, Negi PC, Marwaha R. Oral tadalafil in pulmonary artery hypertension: a prospective study. Indian Heart J. 2007; 59 (4):329–335. [PubMed] [Google Scholar]

32. Bharani A, Patel A, Saraf J, Jain A, Mehrotra S, Lunia B. Efficacy and safety of PDE-5 inhibitor tadalafil in pulmonary arterial hypertension. Indian Heart J. 2007; 59 (4):323–328. [PubMed] [Google Scholar]

33. Galiè N, Brundage BH, Ghofrani HA, et al.Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009; 119 (22):2894–2903. [PubMed] [Google Scholar]

34. Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterial hypertension. Pediatr Cardiol. 2012; 33 (5):683–688. [PMC free article] [PubMed] [Google Scholar]

35. Shlobin OA, Brown AW, Weir N, Ahmad S, Lemma M, Nathan SD. Transition of PH patients from sildenafil to tadalafil: feasibility and practical considerations. Lung. 2012; 190 (5):573–578. [PubMed] [Google Scholar]

36. Oudiz RJ, Brundage BH, Galiè N, et al.PHIRST Study Group Tadalafil for the treatment of pulmonary arterial hypertension a double-blind 52-week uncontrolled extension study. J Am Coll Cardiol. 2012; 60 (8):768–774. [PubMed] [Google Scholar]

37. Sabri MR, Beheshitan E. Comparison of the therapeutic and side effects of tadalafil and sildenafil in children and adolescents with pulmonary arterial hypertension. Pediatr Cardiol. 2014; 35 (4):699–704. [PubMed] [Google Scholar]

38. Shapiro S, Traiger G, Hill W, Zhang L, Doran AK. Safety, tolerability, and efficacy of overnight switching from sildenafil to tadalafil in patients with pulmonary arterial hypertension. Cardiovasc Ther. 2013; 31 (5):274–279. [PubMed] [Google Scholar]

39. Lichtblau M, Harzheim D, Ehlken N, et al. Safety and long-term efficacy of transition from sildenafil to tadalafil due to side effects in patients with pulmonary arterial hypertension. Lung. 2015; 195 (1):105–112. [PubMed] [Google Scholar]

40. Caojin Z, Yigao H, Tao H, et al. Effects of low doses of aerosolized iloprost combined with tadalafil in treatment of adult congenital heart disease with severe pulmonary arterial hypertension. Chin Med J (Engl) 2014; 127 (5):975–977. [PubMed] [Google Scholar]

41. Zhuang Y, Jiang B, Gao H, Zhao W. Randomized study of adding tadalafil to existing ambrisentan in pulmonary arterial hypertension. Hypertens Res. 2014; 37 (6):507–512. [PubMed] [Google Scholar]

42. Tay EL, Geok-Mui MK, Poh-Hoon MC, Yip J. Sustained benefit of tadalafil in patients with pulmonary arterial hypertension with prior response to sildenafil: a case series of 12 patients. Int J Cardiol. 2008; 125 (3):416–417. [PubMed] [Google Scholar]

43. Singh TS, Kumar D, Basu S, Panja M, Mitra B. Tadalafil in the management of severe pulmonary artery hypertension. Indian Heart J. 2006; 58 (1):52–53. [PubMed] [Google Scholar]

44. de Carvalho AC, Hovnanian AL, Fernandes CJ, Lapa M, Jardim C, Souza R. Tadalafil as treatment for idiopathic pulmonary arterial hypertension. Arq Bras Cardiol. 2006; 87 (5):e195–e197. [PubMed] [Google Scholar]

45. Affuso F, Palmieri EA, Di Conza P, Guardasole V, Fazio S. Tadalafil improves quality of life and exercise tolerance in idiopathic pulmonary arterial hypertension. Int J Cardiol. 2006; 108 (3):429–431. [PubMed] [Google Scholar]

46. Palmieri EA, Affuso F, Fazio S, Lembo D. Tadalafil in primary pulmonary arterial hypertension. Ann Intern Med. 2004; 141 (9):743–744. [PubMed] [Google Scholar]

47. Pepke-Zaba J, Beardsworth A, Chan M, Angalakuditi M. Tadalafil therapy and health-related quality of life in pulmonary arterial hypertension. Curr Med Res Opin. 2009; 25 (10):2479–2485. [PubMed] [Google Scholar]

48. Berman-Rosenzweig E, Arneson C, Klinger JR. Effects of dose and age on adverse events associated with tadalafil in the treatment of pulmonary arterial hypertension. Pulm Circ. 2014; 4 (1):45–52. [PMC free article] [PubMed] [Google Scholar]

49. Mathai SC, Hassoun PM, Puhan MA, Zhou Y, Wise RA. Gender differences in response to tadalafil in pulmonary arterial hypertension. Chest. 2015; 147 (1):188–197. [PMC free article] [PubMed] [Google Scholar]

50. Spence R, Mandagere A, Harrison B, Dufton C, Boinpally R. No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers. J Pharm Sci. 2009; 98 (12):4962–4974. [PubMed] [Google Scholar]

51. Kohno H, Ichida F, Hirono K, et al. Plasma concentrations of tadalafil in children with pulmonary arterial hypertension. Ther Drug Monit. 2014; 36 (5):576–583. [PubMed] [Google Scholar]

52. Bendayan D, Shitrit D, Kramer MR. Combination therapy with prostacyclin and tadalafil for severe pulmonary arterial hypertension: a pilot study. Respirology. 2008; 13 (6):916–918. [PubMed] [Google Scholar]

53. Affuso F, Cirillo P, Ruvolo A, Carlomagno G, Fazio S. Long term combination treatment for severe idiopathic pulmonary arterial hypertension. World J Cardiol. 2010; 2 (3):68–70. [PMC free article] [PubMed] [Google Scholar]

54. Faruqi S, Fathi H, Morice AH. Combination of sitaxentan and tadalafil for idiopathic pulmonary arterial hypertension following relapse on bosentan. Int J Cardiol. 2010; 144 (3):e43–e45. [PubMed] [Google Scholar]

55. Maki H, Yao A, Inaba T. Initial and programmed combination therapy with oral drugs for severe idiopathic pulmonary arterial hypertension. Int Heart J. 2011; 52 (5):323–326. [PubMed] [Google Scholar]

56. Barst RJ, Oudiz RJ, Beardsworth A, et al.Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension. J Heart Lung Transplant. 2011; 30 (6):632–643. [PubMed] [Google Scholar]