Frequently Asked Questions about ADCIRCA^® (tadalafil)

For answers to common questions about ADCIRCA, please click the links below:

What is the indication for ADCIRCA?
What is the dosing for ADCIRCA?
Are there any drug-drug interactions with ADCIRCA?
Can ADCIRCA be taken with other PAH medications?
Can patients drink alcohol while taking ADCIRCA?
What are the most common side effects with ADCIRCA?
What is the mechanism of action for ADCIRCA?
How is ADCIRCA metabolized?
How does ADCIRCA affect systolic and diastolic blood pressure?
Can ADCIRCA be used safely in older patients?
Which classes of PAH can ADCIRCA be used to treat?
How should ADCIRCA be stored?
Are pharmacies equipped to answer questions about ADCIRCA?
What clinical benefits can be expected with ADCIRCA?
Does ADCIRCA offer clinical benefits beyond improved exercise ability?
Is there an assistance program for patients who cannot afford their co-pay?
Is there an assistance program for patients who are uninsured or who have inadequate insurance coverage?
What patient support programs are available for patients and their caregivers?

What is the indication for ADCIRCA?

ADCIRCA^® (tadalafil) is a phosphodiesterase 5 inhibitor (PDE-5i) indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).²

What is the dosing for ADCIRCA?

ADCIRCA is the only phosphodiesterase 5 inhibitor (PDE-5i) approved for PAH with once-daily dosing. The recommended starting and maintenance dose for most patients for ADCIRCA is 40 mg (two 20-mg tablets). ADCIRCA can be taken with or without food. Dividing the 40-mg dose for ADCIRCA over the course of the day is not recommended.²

Tadalafil is metabolized predominately by CYP3A in the liver. Use of ADCIRCA with potent CYP3A inhibitors, such as ketoconazole and itraconazole, should be avoided. For patients on ADCIRCA therapy that require treatment with ritonavir, ADCIRCA should be discontinued at least 24 hours prior to starting ritonavir. For patients on ritonavir therapy that require treatment with ADCIRCA, start ADCIRCA at 20 mg once a day. Use of ADCIRCA with potent inducers of CYP3A, such as rifampin, should be avoided.²

The use of ADCIRCA is not recommended for patients with severe renal or hepatic impairment. Please see Full Prescribing Information for dosing recommendations for patients with mild to moderate renal or hepatic impairment.²

Are there any drug-drug interactions with ADCIRCA?

ADCIRCA may have interactions with²:

• Nitrates and guanylate cyclase (GC) stimulators (such as riociguat). Nitrates and GC stimulators are contraindicated. Do not use nitrates within 48 hours of the last dose of ADCIRCA
• Alpha-blockers
• Antihypertensives
• Alcohol
• Ritovanir
• Potent inhibitors of CYP3A
• Potent inducers of CYP3A

Please see DRUG INTERACTIONS in Full Prescribing Information.

Can ADCIRCA be taken with other PAH medications?

ADCIRCA has been studied in patients taking background bosentan therapy. Bosentan (125 mg twice daily) reduced tadalafil (40 mg once daily) systemic exposure by 42% and C_max by 27% following multiple-dose co-administration. In the pivotal trial for ADCIRCA, more than half (53%) of subjects were receiving concomitant bosentan therapy. Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms (eg, bosentan).²

ADCIRCA is contraindicated in patients taking guanylate cyclase (GC) stimulators. Do not use ADCIRCA in patients who are using a GC stimulator, such as riociguat. ADCIRCA may potentiate the hypotensive effects of GC stimulators.²

Can patients drink alcohol while taking ADCIRCA?

Both alcohol and tadalafil are mild vasodilators. When mild vasodilators are taken in combination, blood pressure-lowering effects are increased. Substantial consumption of alcohol (eg, 5 units or greater) in combination with ADCIRCA can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.²

Please see DRUG INTERACTIONS in Full Prescribing Information.

What are the most common side effects with ADCIRCA?

The most common adverse events with ADCIRCA (reported by ≥9% of patients on ADCIRCA and more frequently than placebo by 2%, respectively) include²:

• Headache (42% vs 15%)
• Myalgia (14% vs 4%)
• Nasopharyngitis (13% vs 7%)
• Flushing (13% vs 2%)
• Respiratory tract infection (13% vs 6%)
• Extremity pain (11% vs 2%)
• Nausea (11% vs 6%)
• Back pain (10% vs 6%)
• Dyspepsia (10% vs 2%)
• Nasal congestion (9% vs 1%)

What is the mechanism of action for ADCIRCA?

ADCIRCA is an inhibitor of phosphodiesterase 5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). PAH is associated with the impaired release of nitric oxide by the vascular endothelium in the pulmonary vasculature. Inhibition of PDE-5 by tadalafil increases the concentrations of cGMP, resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.²

How is ADCIRCA metabolized?

ADCIRCA is predominately metabolized by CYP3A to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggest that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.

Use of ADCIRCA with potent CYP3A inhibitors, such as ketoconazole and itraconazole, should be avoided. For patients on ADCIRCA therapy that require treatment with ritonavir, ADCIRCA should be discontinued at least 24 hours prior to starting ritonavir. For patients on ritonavir therapy that require treatment with ADCIRCA, start ADCIRCA at 20 mg once a day. Use of ADCIRCA with potent inducers of CYP3A, such as rifampin, should be avoided.²

How does ADCIRCA affect systolic and diastolic blood pressure?

PDE-5 inhibitors, including tadalafil, have mild systemic vasodilatory properties that may result in transient decreases in blood pressure.

Prior to prescribing ADCIRCA, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.

Patients with severely impaired autonomic control of blood pressure or with left ventricular outflow obstruction (eg, aortic stenosis and idiopathic hypertrophic subaortic stenosis) may be particularly sensitive to the actions of vasodilators, including PDE-5 inhibitors.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of ADCIRCA to patients with veno-occlusive disease, administration of ADCIRCA to such patients is not recommended. Should signs of pulmonary edema occur when ADCIRCA is administered, the possibility of associated PVOD should be considered.²

For effects on blood pressure when administered with nitrates, antihypertensives, alcohol, or alpha-blockers, please see PHARMACODYNAMICS in Full Prescribing Information.

Can ADCIRCA be used safely in older patients?

In the pivotal clinical study for ADCIRCA, 28% of the total number of subjects were 65 and over, while 8% were 75 and over. No overall differences in safety were observed between subjects over 65 years of age compared with younger subjects or those over 75 years of age. No dose adjustment is warranted based on age alone; however, a greater sensitivity to medication in some older individuals should be considered.²

Please see USE IN SPECIFIC POPULATIONS in Full Prescribing Information.

Which classes of PAH can ADCIRCA be used to treat?

ADCIRCA can be used in all functional classes of PAH. Studies establishing effectiveness included predominately patients with NYHA Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).²

How should ADCIRCA be stored?

ADCIRCA should be stored at 77°F (25°C); excursions permitted to 59°F-86°F (15°C-30°C) [see USP Controlled Room Temperature]. ADCIRCA should be kept out of reach of children.²

Are pharmacies equipped to answer questions about ADCIRCA?

ADCIRCA is available through retail and specialty pharmacies. Retail pharmacies are capable of answering patients’ questions about ADCIRCA. Specialty pharmacies typically provide the special services listed below:

• Scheduled home deliveries
• Monthly refill reminder call
• Help with billing insurance claims
• Access to additional PAH therapies as disease progresses

ADCIRCA is available through specialty pharmacies, including the specialty pharmacies listed below (listed alphabetically)*:

• Accredo^®
• CVS Specialty^®

^* This is not an endorsement of any pharmacy or the quality of support it may provide.

What clinical benefits can be expected with ADCIRCA?

The pivotal clinical study for ADCIRCA showed that ADCIRCA increases exercise capacity in patients with PAH. The primary efficacy endpoint was the change from baseline at week 16 in 6MWD. In the ADCIRCA 40-mg treatment group, the placebo-adjusted mean increase in 6MWD was 33 meters (P=0.0004). The improvement in 6MWD was apparent at 8 weeks of treatment and then maintained at week 12 and week 16.

Does ADCIRCA offer clinical benefits beyond improved exercise ability?

The pivotal clinical study for ADCIRCA showed that ADCIRCA decreased clinical worsening in patients with PAH. There was less clinical worsening at 16 weeks (defined as death, lung transplantation, atrial septostomy, hospitalization because of worsening PAH, initiation of new PAH therapy [prostacyclin or analog, endothelin receptor antagonist, PDE-5 inhibitor], or worsening WHO functional class) in the ADCIRCA 40-mg group compared with the placebo group (p=0.041) and the groups that used lower doses of ADCIRCA.

Is there an assistance program for patients who cannot afford their co-pay?

Through the ADCIRCA Co-Pay Assistance Program, eligible patients on commercial/private insurance plans* have a $5 co-pay per prescription fill for 12 fills (program covers the difference in co-pay above $5 up to $800 monthly). Click for more information.

*Patients are not eligible for this program if their prescriptions are reimbursed under Medicare, Medicaid, VA, DoD (TRICARE), Indian Health Service, or similar federal or state programs.

Is there an assistance program for patients who are uninsured or who have inadequate insurance coverage?

Our ASSIST Advisors can provide information on assistance programs and eligibility requirements to your office staff or directly to your patients.* ASSIST Advisors can also provide information on insurance benefits, including prior authorization, claim denials, appeals, and step edit requirements. Click for more information.

*Patients receiving reimbursement under Medicare, Medicaid, VA, DoD (TRICARE), Indian Health Services, or similar federal or state programs, may not be eligible for some assistance. Some portion of this patient assistance may be administered by an independent third party organization.

What patient support programs are available for patients and their caregivers?

The Pulmonary Hypertension Association (PHA)

The PHA is a leading community-based organization for patients with PAH. Its mission is to find ways to prevent and cure PAH, while providing hope to the community of affected individuals. To that end, the PHA offers the following services:

• Support groups, both local and online
• Educational programs for patients and families
• Tips on getting the most from your health insurance program
• Advocacy programs for lobbying members of Congress
• Updates on new developments in the field of PAH

For more information, visit www.PHAssociation.org.

The National Heart, Lung, and Blood Institute (NHLBI)

The NHLBI is part of the National Institutes of Health (NIH), the agency of the US Department of Health and Human Services that is largely responsible for conducting medical research. The NHLBI website has
easy-to-understand information about various diseases that affect the heart and lungs. To learn more, visit www.nhlbi.nih.gov and search for “PAH.”

References:

• Data on file, June 2016.
• ADCIRCA [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017.