"The U.S. Food and Drug Administration today approved Opsumit (macitentan), a new drug to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive and debilitating disease that can lead to death or the need for lung transpla"...
- Patient Information:
Details with Side Effects
Discuss with patients the appropriate action to take in the event that they experience anginal chest pain requiring nitroglycerin following intake of ADCIRCA. At least 48 hours should elapse after the last dose of ADCIRCA before taking nitrates. If a patient has taken ADCIRCA within 48 hours, administer nitrates under close medical supervision with appropriate hemodynamic monitoring. Patients who experience anginal chest pain after taking ADCIRCA should seek immediate medical attention.
PDE5 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, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors.
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary venoocclusive 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.
There is a lack of data on safety and efficacy in the following groups who were specifically excluded from the PAH clinical trials:
- Patients with clinically significant aortic and mitral valve disease
- Patients with pericardial constriction
- Patients with restrictive or congestive cardiomyopathy
- Patients with significant left ventricular dysfunction
- Patients with life-threatening arrhythmias
- Patients with symptomatic coronary artery disease
- Patients with hypotension ( < 90/50 mm Hg) or uncontrolled hypertension
Use with Alpha Blockers and Antihypertensives
PDE5 inhibitors, including ADCIRCA, and alpha–adrenergic blocking agents are vasodilators with blood pressure– lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see CLINICAL PHARMACOLOGY and DRUG INTERACTIONS], which may lead to symptomatic hypotension (e.g., fainting). Safety of combined use of PDE5 inhibitors and alpha blockers may be affected by other variables, including intravascular volume depletion and use of other antihypertensive drugs [see DRUG INTERACTIONS].
Use With Alcohol
Use With Potent CYP3A Inhibitors Or Inducers
Co-Administration Of ADCIRCA In Patients On Ritonavir
In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Co-Administration Of Ritonavir In Patients On ADCIRCA
Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Other Potent Inhibitors Of CYP3A
Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole and itraconazole, avoid use of ADCIRCA [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Potent Inducers Of CYP3A
Use In Renal Impairment
In Patients With Mild Or Moderate Renal Impairment
In Patients With Severe Renal Impairment
Avoid use of ADCIRCA because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Use In Hepatic Impairment
In Patients With Mild To Moderate Hepatic Cirrhosis (Child-Pugh Class A and B)
Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis, consider a starting dose of 20 mg once daily ADCIRCA [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
In Patients With Severe Hepatic Cirrhosis (Child-Pugh Class C)
Effects On The Eye
Physicians should advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors [see ADVERSE REACTIONS].
Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.
Physicians should advise patients to seek immediate medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including ADCIRCA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see ADVERSE REACTIONS].
Combination With Other PDE5 Inhibitors
Tadalafil is also marketed as CIALIS. The safety and efficacy of taking ADCIRCA together with CIALIS or other PDE5 inhibitors have not been studied. Inform patients taking ADCIRCA not to take CIALIS or other PDE5 inhibitors.
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.
ADCIRCA should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease).
Effects On Bleeding
PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. ADCIRCA has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although ADCIRCA has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment.
Patient Counseling Information
See FDA-Approved Patient Labeling (PATIENT INFORMATION)
- Inform patients of contraindication of ADCIRCA with any use of organic nitrates.
- Inform patients that tadalafil is also marketed as CIALIS for erectile dysfunction (ED) and for the signs and symptoms of benign prostatic hyperplasia (BPH). Advise patients taking ADCIRCA not to take CIALIS or other PDE5 inhibitors.
- Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking ADCIRCA. Such an event may be a sign of NAION.
- Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking ADCIRCA. These events may be accompanied by tinnitus and dizziness.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 5–fold for mice, and 7– and 14–fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg.
Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays.
Impairment Of Fertility
There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 6–fold for males or 17–fold for females the exposures at the MRHD of 40 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment–related non–reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20–100% of the dogs that resulted in a decrease in spermatogenesis in 40–75% of the dogs at doses of ≥ 10 mg/kg/day. Systemic exposure (based on AUC) at no–observed–adverse-effect–level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 40 mg.
There were no treatment–related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.
Use In Specific Populations
Pregnancy Category B
Animal reproduction studies in rats and mice revealed no evidence of fetal harm. There are, however, no adequate and well-controlled studies of tadalafil in pregnant women. Because animal reproduction studies are not always predictive of human response, tadalafil should be used during pregnancy only if clearly needed.
Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis. In one of two perinatal/postnatal developmental studies in rats, postnatal pup survival decreased following maternal exposure to unbound tadalafil concentrations greater than 5 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 8 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance [see Nonclinical Toxicology].
It is not known whether tadalafil is excreted into human milk. While tadalafil or some metabolite of tadalafil was excreted into rat milk, drug levels in animal breast milk may not accurately predict levels of drug in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when ADCIRCA is administered to a nursing woman.
Safety and effectiveness of ADCIRCA in pediatric patients have not been established.
Of the total number of subjects in the clinical study of tadalafil for pulmonary arterial hypertension, 28 percent were 65 and over, while 8 percent were 75 and over. No overall differences in safety were observed between subjects over 65 years of age compared to younger subjects or those over 75 years of age. No dose adjustment is warranted based on age alone; however, a greater sensitivity to medications in some older individuals should be considered. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
For patients with mild or moderate renal impairment, start ADCIRCA at 20 mg once daily. Increase the dose to 40 mg once daily based upon individual tolerability [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
In patients with severe renal impairment, avoid use of ADCIRCA because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A or B), consider a starting dose of ADCIRCA 20 mg once daily. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, thus avoid use of ADCIRCA in such patients [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 12/5/2013
This monograph has been modified to include the generic and brand name in many instances.
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