Treatments for Pulmonary Hypertension
Issued by PHA’s Scientific Leadership Council. Information is based on the United States Food and Drug Administration drug labeling.
Last updated February 2012
What is tadalafil?
Tadalafil (Adcirca™) is a phosphodiesterase-5 inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) in World Health Organization (WHO) Group 1 patients in order to improve exercise ability. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).
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® which is FDA approved for the treatment of erectile dysfunction but not for the treatment of PAH.
How does tadalafil work?
Phosphodiesterase 5 (PDE-5) is a substance produced in the lungs and other parts of the body that breaks down (metabolizes) another substance called cyclic guanosine monophosphate (GMP). Cyclic GMP causes the blood vessels (arteries) to relax, that is, to widen. Tadalafil inhibits PDE-5, so that more cyclic GMP is available for the blood vessels inside the lungs to relax, leading to widening of the blood vessels. Relaxing and widening of the blood vessels in the lungs makes it easier for the heart to pump blood through the lungs. This reduces blood pressure in the lungs which should lead to improvement in physical activity level and well being.
A multi-center short-term (16 week) randomized study of adult PAH patients demonstrated that tadalafil improved exercise capacity and sense of well being. There was less clinical worsening (defined by events such as hospitalization for PAH, worsening WHO functional class, need for new PAH therapy, lung transplantation or death). Of note, a little more than ½ the patients were already on bosentan at the time the tadalafil was added. Long-term follow-up data involving the patients enrolled in that study must be interpreted cautiously but seems to indicate that patients tolerate tadalafil therapy both with and without bosentan.
How is tadalafil given?
The recommended dose for 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 then advance to the full dose of 2 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, CVS Caremark, Cigna Tel-Drug, CuraScript, Kaiser Permanente Specialty Pharmacy, Precision Rx, Walgreens Specialty Pharmacy (Medmark), and WellCare.
Will insurance pay for tadalafil?
It is expected that most insurance plans will pay for tadalafil prescriptions; however, plans with a set co-payment may result in additional cost to the patient.
Medicaid and most state-run insurance plans will pay for tadalafil. Medicare will also cover tadalafil in most cases under the part D component of that program.
Caring Voice Coalition (888-267-1440), an organization that provides grants to assist with drug cost for patients with chronic illnesses, may also provide coverage if the patient qualifies for such assistance.
What are the frequent side effects of tadalafil?
Tadalafil is generally well tolerated.
The most common side effects reported with tadalafil were headache, muscle pain, nasal swelling, flushing, respiratory tract infection, extremity pain, nausea, back pain, upset stomach, and nasal congestion.
Other potential side effects deserve specific mention as noted below.
A reduction in blood pressure may occur as tadalafil opens up blood vessels (arteries) throughout the body. Careful consideration should be used for patients with resting systemic hypotension (low blood pressure, for example less than 90/50 mmHg), fluid depletion, severe left ventricular outflow obstruction or autonomic dysfunction. Taking certain drugs such as nitrates, nitric oxide donors or alpha blockers along with tadalafil can cause a significant drop in systemic blood pressure, which 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 organic nitrates is CONTRAINDICATED.
Prolonged erection (greater than 4 hours) in a male patient is a rare but very serious side effect; if this should happen to you, you should 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?
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.
The safety and effectiveness of tadalafil in pediatric PAH patients has not been established.
Hepatic (liver) Impairment
- Mild or moderate (Child Pugh Class A or B): Limited experience. Consider starting with a dose of 20 mg once daily
- Severe (Child Pugh Class C): Avoid use.
Renal (kidney) Impairment
- Mild to moderate renal impairment (creatinine clearance 31 to 80 ml/min): Start with 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
- Severe renal impairment: (creatinine clearance < 30 ml or on hemodialysis): Avoid use due to increased tadalafil exposure, limited clinical experience, and inability to influence clearance by dialysis.
Tadalafil is not recommended in patients with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis.
Could a patient be allergic to tadalafil?
This is possible, although unlikely. Any medication can cause side effects or sensitivities and you should check with your doctor if you experience a problem such as a rash or throat tightening.
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 other antihypertension (to systemic lower blood pressure) medications including alpha blockers because of additive blood pressure-lowering effects.
Tadalafil is metabolized predominantly by CYP3A in the liver; therefore, important interactions may occur with medications that affect this pathway. Ritonavir initially inhibits and later induces CYP3A. For patients on tadalafil therapy that require treatment with ritonavir, tadalafil should be discontinued at least 24 hours prior to starting ritonavir. For patients on ritonavir therapy that require treatment with tadalafil, start tadalafil at 20 mg once a day. Use of tadalafil with potent CYP3A inhibitors, such as ketoconazole and itraconazole, should be avoided. Conversely, the use of tadalafil with potent CYP3A inducers, such as rifampin, should also be avoided.
Concomitant use of bosentan and tadalafil may result in decreased tadalafil blood levels. Changes in the usual dosing of these 2 drugs when used in combination is not typically necessary.
Can tadalafil be taken with other medications?
As stated above, you should not be taking nitrates in any form while taking tadalafil. Caution should also be used when taking tadalafil in combination with other medications that lower blood pressure. Although a drug interaction has been demonstrated with tadalafil and bosentan, dose adjustments are presently not recommended for either drug.
Is there any risk of blindness when using tadalafil?
There have been rare reports of blindness with use of all the currently available phosphodiesterase-5 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. NAION has not been reported thus far with Adcirca®.
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 between genders. Peer-reviewed studies have not shown any effect on sexual function in women who have taken tadalafil.
Summary of Clinical Trial
Randomized placebo controlled double blind 16 week study conducted in 405 patients with group I PAH. The majority of patients were WHO functional class III (65%) or II (32%). Background therapy with bosentan was allowed; 53% were on bosentan therapy. Patients were randomized to placebo, 2.5, 10, 20 or 40 mg once daily.
Primary efficacy endpoint: Change in 6 min walk at 16 weeks. In the 40 mg treatment group, a placebo adjusted mean change increase in 6 minute walk distance was 33 meters. In the subgroup of patients on bosentan, the placebo adjusted increase in 6 minute walk was 23 meters. In the subgroup not on bosentan, the placebo adjusted increase in 6 minute walk was 44 meters.
There was a statistically significant delay in the composite endpoint of time to clinical worsening in the 40 mg treatment group compared to the placebo group and the lower dosage groups. An improvement in mean pulmonary artery pressure and pulmonary vascular resistance was observed in both the 20 mg and 40 mg dosage groups; there was also an improvement in cardiac index in the 40 mg group. Improvements in quality of life measures were also seen in the 40 mg group. The extension study suggested good continued tolerability.
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