Entadfi

Pregnancy

Risk Summary

ENTADFI is contraindicated in pregnancy and not indicated for use in females [see Contraindications ].  Based on animal studies and its mechanism of action, finasteride, a component of ENTADFI, may cause abnormal development of external genitalia in a male fetus if administered to a pregnant female [see Clinical Pharmacology ].  In animal reproduction studies, oral administration of finasteride to pregnant rats during the period of major organogenesis resulted in a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring at maternal doses approximately 0.1 to 86 times the maximum recommended human dose (MRHD) of 5 mg/day; decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development in male offspring at maternal doses approximately 0.03 times the MRHD and decreased anogenital distance in male offspring at maternal doses approximately 0.003 times the MRHD (see Data).  Finasteride is a Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. Abnormal male genital development is an expected consequence when conversion of testosterone to 5α-dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those reported in male infants with genetic 5α-reductase deficiency.

In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures up to 44 times the maximum recommended human dose (MRHD) of 5 mg/day (See Data).

Females of reproductive potential, including pregnant females, should not handle crushed or open ENTADFI capsules because of possible exposure of a male fetus [see Warnings and Precautions ].

Data

Animal Data

Finasteride:

In an embryo-fetal development study, pregnant rats received finasteride during the period of major organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 0.1 to 86 times the maximum recommended human dose (MRHD) of 5 mg/day (based on AUC at animal doses of 0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17 of gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral maternal doses approximately 0.03 times the MRHD (based on AUC at animal dose of 0.03 mg/kg/day), male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats that received approximately 0.003 times the MRHD (based on AUC at animal dose of 0.003 mg/kg/day). No abnormalities were observed in female offspring at any maternal dose of finasteride.

Slightly decreased fertility was observed in male offspring after administration of about 3 times the MRHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late gestation and lactation. No effects on fertility were seen in female offspring under these conditions.

No evidence of male external genital malformations or other abnormalities were observed in rabbit fetuses exposed to finasteride during the period of major organogenesis (gestation days 6-18) at maternal oral doses up to 100 mg/kg/day, (finasteride exposure levels were not measured in rabbits). However, this study may not have included the critical period for finasteride effects on development of male external genitalia in the rabbit.

The fetal effects of maternal finasteride exposure were evaluated during the period of embryonic and fetal development from gestation day 20-100 in the rhesus monkey. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated maximal blood concentration of 1.86 ng/mL or about 143 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male fetuses. However, oral administration of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses at any dose.

Tadalafil:

Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given orally to pregnant rats or mice at exposures up to 44 times the indicated dose of 5 mg/day during organogenesis. In a prenatal/postnatal developmental study in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 40 times the indicated dose based on AUC. Signs of maternal toxicity occurred at doses greater than 64 times the indicated dose based on AUC. Surviving offspring had normal development and reproductive performance.

In another rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 64- and 40 fold exposure multiples, respectively, of the human AUC for the indicated dose of 5 mg.

Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.

Lactation

Risk Summary

ENTADFI is not indicated for use in females.

Females and Males of Reproductive Potential

Infertility

Males

Tadalafil:

There have been no studies evaluating the effect of ENTADFI, including tadalafil, on fertility in men [see Clinical Pharmacology ].

Based on studies in animals, a decrease in spermatogenesis was observed in dogs, but not in rats [see Nonclinical Toxicology ].

Fertility Effects

Finasteride:

Treatment with finasteride for 24 weeks to evaluate semen parameters in healthy male volunteers revealed no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL (22.1%) median decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate was observed. These parameters remained within the normal range and were reversible upon discontinuation of therapy with an average time to return to baseline of 84 weeks.

Tadalafil:

Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. There was no adverse effect of tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone. The clinical significance of the decreased sperm concentrations in the two studies is unknown. 

Pediatric Use

The safety and effectiveness of ENTADFI have not been established in patients less than 18 years of age.

Geriatric Use

ENTADFI is a combination of finasteride and tadalafil.

Finasteride:

Of the total number of finasteride-treated patients in clinical studies for BPH, 1480 and 105 patients were 65 and over and 75 and over, respectively. No overall differences in safety or effectiveness of finasteride have been observed between patients 65 years of age and older and younger adult patients [see Clinical Pharmacology 12.3].

Tadalafil:

Of the total number of tadalafil-treated patients in clinical studies which included an indication for which ENTADFI is not approved, approximately 40 percent were over 65 years of age, while approximately 10 percent were 75 years of age and over. No overall differences in safety or effectiveness of tadalafil have been observed between patients over 65 years of age and younger adult patients. However, in placebo-controlled studies with tadalafil for use as needed for a use for which ENTADFI is not approved, diarrhea was reported more frequently in patients 65 years of age and older who were treated with tadalafil (2.5% of patients). A greater sensitivity in some older individuals should be considered [see Clinical Pharmacology ].

Hepatic Impairment

The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. However, finasteride is extensively metabolized in the liver. Exercise caution in the administration of ENTADFI in those patients with mild to moderate hepatic impairment (Child Pugh Class A or B). Insufficient tadalafil data are available for patients with severe hepatic impairment (Child Pugh Class C). Therefore, ENTADFI use is not recommended in these patients. [see Clinical Pharmacology ].

Renal Impairment

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, ENTADFI use is not recommended in patients with creatinine clearance less than 50 mL/min or on hemodialysis [see Clinical Pharmacology ].

Cardiovascular Risk

ENTADFI is contraindicated in patients taking any form of organic nitrate, either regularly and/or intermittently [see Contraindications ]. Discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of ENTADFI. In such a patient, who has taken ENTADFI, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of ENTADFI before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, advise patients who experience anginal chest pain after taking ENTADFI to seek immediate medical attention [see Contraindications ].

Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors.

The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for tadalafil, and therefore until further information is available, ENTADFI is not recommended for the following groups of patients:

• myocardial infarction within the last 90 days
• unstable angina or angina occurring during sexual intercourse
• New York Heart Association Class 2 or greater heart failure in the last 6 months
• uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension
• stroke within the last 6 months.

As with other PDE5 inhibitors, tadalafil, a component of ENTADFI, has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects [see Clinical Pharmacology ]. While this effect should not be of consequence in most patients, prior to prescribing ENTADFI, 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 may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors.

 Potential for Drug Interactions when Taking ENTADFI

ENTADFI provides continuous plasma tadalafil levels. Consider this when evaluating the potential for ENTADFI interactions with medications (e.g., nitrates, alpha-blockers, anti-hypertensives and strong inhibitors of CYP3A4) and with substantial consumption of alcohol [see Drug Interactions ].

 Concomitant Use with Alpha-blockers or Antihypertensives

Discuss with patients the potential for ENTADFI to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications [see Drug Interactions and Clinical Pharmacology ].

Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including ENTADFI, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see Drug Interactions and Clinical Pharmacology ], which may lead to symptomatic hypotension (e.g., fainting). Consider the following:

BPH

• The efficacy of the coadministration of an alpha-blocker and ENTADFI for the treatment of BPH has not been adequately studied, and due to the potential vasodilatory effects of combined use resulting in blood pressure lowering, the combination of ENTADFI and alpha-blockers is not recommended for the treatment of BPH [see Drug Interactions , and Clinical Pharmacology ].
• Discontinue alpha-blockers at least one day prior to starting ENTADFI for once daily use for the treatment of BPH.

 Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH

Prior to initiating treatment with ENTADFI for BPH, consider whether the patient has other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.

Carefully monitor patients with large residual urinary volume and/or severely diminished urinary flow for obstructive uropathy. These patients may not be candidates for ENTADFI therapy.

 Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection

In clinical studies, finasteride, a component of ENTADFI, reduced serum PSA concentration by approximately 50% within six months of treatment. This decrease is predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals.

For interpretation of serial PSAs in men taking ENTADFI, a new PSA baseline should be established at least six months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on ENTADFI may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5α-reductase inhibitor. Non-compliance with ENTADFI therapy may also affect PSA test results. To interpret an isolated PSA value in patients treated with ENTADFI for six months or more, double the PSA values for comparison with normal ranges in untreated men. These adjustments preserve the utility of PSA to detect prostate cancer in men treated with ENTADFI.

ENTADFI may also cause decreases in serum PSA in the presence of prostate cancer.

The ratio of free to total PSA (percent free PSA) remains constant even under the influence of ENTADFI. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing ENTADFI therapy, no adjustment to its value appears necessary.

 Increased Risk of High-Grade Prostate Cancer

Use of 5α-reductase inhibitors, including ENTADFI, may increase the risk of development of high-grade prostate cancer. Men aged 55 years and over with a normal digital rectal examination and PSA less than or equal to 3.0 ng/mL at baseline taking finasteride, a component of ENTADFI (5 mg daily) in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of Gleason score 8 to 10 prostate cancer (finasteride 1.8% vs placebo 1.1%) [See Adverse Reactions ]. Similar results were observed in a 4-year placebo-controlled clinical trial with a different 5α-reductase inhibitor. Whether the effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established.

 Risk to Male Fetus from Topical ENTADFI Exposure to Pregnant Females

ENTADFI is contraindicated in pregnant females and is not indicated for use in females. Based on animal studies and the mechanism of action of finasteride, ENTADFI may cause abnormal development of external genitalia in a male fetus if administered to a pregnant female. Pregnant females should not handle crushed or open ENTADFI capsules because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. If a pregnant female comes in contact with crushed or broken ENTADFI capsules, the contact area should be washed immediately with soap and water [see Contraindications , Use in Specific Populations ].

 Hypersensitivity Reactions

ENTADFI is contraindicated in patients with a history of hypersensitivity reactions to finasteride, tadalafil, or to any component of ENTADFI [see Contraindications ]. Immediately discontinue ENTADFI if a hypersensitivity reaction occurs. Hypersensitivity reactions have included Stevens-Johnson syndrome, exfoliative dermatitis, pruritis, urticaria, and angioedema [see Adverse Reactions ].

 Prolonged Erection and Priapism

Instruct patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention. Use ENTADFI 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).

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.

 Ocular Adverse Reactions

Advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including ENTADFI, and seek 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 rare condition and 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. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 in males aged 50 years and older.

Consider whether patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, use PDE5 inhibitors, including ENTADFI, with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population; however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including ENTADFI, for this uncommon condition.

Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use of ENTADFI in these patients is not recommended.

An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of "crowded" optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [see Adverse Reactions ].

 Sudden Hearing Loss

Advise patients to stop taking ENTADFI and seek prompt 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 ENTADFI. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, such as ENTADFI, or to other factors [see Adverse Reactions ].

 Concomitant Use with Alcohol

Inform patients that both alcohol and tadalafil, a PDE5 inhibitor and a component of ENTADFI, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with ENTADFI can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Drug Interactions ].

 Concomitant Use with Strong Inhibitors of Cytochrome P450 3A4 (CYP3A4)

Tadalafil, a component of ENTADFI, is metabolized predominantly by CYP3A4 in the liver. ENTADFI is not recommended in patients taking strong inhibitors of CYP3A4 [see Drug Interactions , Clinical Pharmacology ].

 Effects on Bleeding

Studies in vitro have demonstrated that tadalafil, a component of ENTADFI, is a selective inhibitor of PDE5. PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. ENTADFI has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although tadalafil, a component of ENTADFI, has not been shown to increase bleeding times in healthy subjects, use ENTADFI with caution in patients with bleeding disorders or significant active peptic ulceration after a careful risk-benefit assessment.