ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:Hypotension [see Warnings and Precautions (5.1)] Visual Loss [see Warnings and Precautions (5.3) and Patient Counseling Information (17)] Hearing loss [see Warnings and Precautions (5.4)] Priapism [see Warnings and Precautions (5.6)] Hypotension [see Warnings and Precautions (5.1)] Visual Loss [see Warnings and Precautions (5.3) and Patient Counseling Information (17)] Hearing loss [see Warnings and Precautions (5.4)] Priapism [see Warnings and Precautions (5.6)] The most common adverse reaction is headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Tadalafil was administered to 398 patients with PAH during clinical trials worldwide. In trials of ALYQ(TM), total of 311 and 251 subjects have been treated for at least 182 days and 360 days, respectively. The overall rates of discontinuation because of an adverse event (AE) in the placebo-controlled trial were 9% for ALYQ(TM) 40 mg and 15% for placebo. The rates of discontinuation because of AEs, other than those related to worsening of PAH, in patients treated with ALYQ(TM) 40 mg was 4% compared to 5% in placebo-treated patients.In the placebo-controlled study, the most common AEs were generally transient and mild to moderate in intensity. Table presents treatment-emergent adverse events reported by >=9% of patients in the ALYQ(TM) 40 mg group and occurring more frequently than with placebo.Table 1: Treatment-Emergent Adverse Events Reported by >=9% of Patients in ALYQ(TM) and More Frequent than Placebo by 2%EVENT Placebo (%) ALYQ(TM) 20 mg (%)ALYQ(TM) 40 mg (%)(N=82) (N=82) (N=79) Headache 15 32 42 Myalgia 9 14 Nasopharyngitis 2 13 Flushing 6 13 Respiratory Tract Infection (Upper and Lower) 7 13 Pain in Extremity 5 11 Nausea 10 11 Back Pain 12 10 Dyspepsia 13 10 Nasal Congestion (Including sinus congestion) 0 . 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of tadalafil. These events have been chosen for inclusion either because of their seriousness, reporting frequency, lack of clear alternative causation, or combination of these factors. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to estimate reliably their frequency or establish causal relationship to drug exposure. The list does not include adverse events that are reported from clinical trials and that are listed elsewhere in this section.Cardiovascular and cerebrovascular -- Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil [see Contraindications (4.1)]. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and few were reported to occur shortly after the use of tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of tadalafil and sexual activity. It is not possible to determine whether these events are related directly to tadalafil, to sexual activity, to the patients underlying cardiovascular disease, to combination of these factors, or to other factors.Body as whole -- Hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis Nervous -- Migraine, seizure and seizure recurrence, and transient global amnesiaOphthalmologic -- Visual field defect, retinal vein occlusion, retinal artery occlusion, and NAION [see Warnings and Precautions (5.3) and Patient Counseling Information (17)].Otologic -- Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of tadalafil, to the patients underlying risk factors for hearing loss, combination of these factors, or to other factors [see Warnings and Precautions (5.4) and Patient Counseling Information (17)]. Urogenital -- Priapism [see Warnings and Precautions (5.6)].

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Animal studies showed vascular inflammation in tadalafil-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 1- to 17-fold the human exposure (AUCs) at the MRHD of 40 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1- and 6-month studies at unbound tadalafil exposure of 0.5- to 38-fold the human exposure (AUC) at the MRHD of 40 mg. In 12-month dog study, no disseminated arteritis was observed, but dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 4- to 10-fold the human exposure at the MRHD of 40 mg. The abnormal blood-cell findings were reversible within weeks upon removal of the drug.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis -- Tadalafil was not carcinogenic to rats or mice when administered daily for 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.Mutagenesis -- 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, 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 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 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 years.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tadalafil is an inhibitor of phosphodiesterase type (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.Studies in vitro have demonstrated that tadalafil is selective inhibitor of PDE5. PDE5 is found in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is 10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is 9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, tadalafil inhibits human recombinant PDE11A1 and, to lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.. 12.2 Pharmacodynamics. Effects on Blood Pressure When Administered with NitratesIn clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Do not use ALYQ(TM) in patients taking any form of nitrates [see Contraindications (4.1)].A double-blind, placebo-controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) assessed the interaction between nitroglycerin and tadalafil. Subjects received daily doses of tadalafil 20 mg or matching placebo for days and then were given single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified timepoints following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although few more tadalafil subjects compared to placebo experienced greater blood-pressure lowering effects at this timepoint. After 48 hours, the interaction was not detectable [See Contraindications (4.1)]. Effects on Blood Pressure.The effects of tadalafil on blood pressure alone and administered with antihypertensives, alcohol, and alpha-blockers is shown in Figure 1.a In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed, and dizziness occurred at similar frequency to alcohol alone.b In studies of tadalafil co-administration with doxazosin, the number of subjects with potentially clinically significant standing blood pressure decreases was greater for the combination. Some patients had symptoms associated with the decrease in blood pressure including syncope.Figure 1: Effects of Tadalafil on Blood PressureEffects on Cardiac ElectrophysiologyThe effect of single 100 mg dose of tadalafil (2.5 times the recommended dose) on the QT interval was evaluated at the time of peak tadalafil concentration in randomized, double-blinded, placebo, and active-controlled (intravenous ibutilide) crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). In this study, the mean increase in heart rate associated with 100 mg dose of tadalafil compared to placebo was 3.1 beats per minute. Effects on Exercise Stress TestingThe effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was similar to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates.Effects on VisionSingle oral doses of PDE inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In study to assess the effects of single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (<0.1% of patients).Effects on Sperm CharacteristicsThree studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for months and the study of 20 mg tadalafil for months, results showed decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.Dose-Response RelationshipDose-response relationships, between 20 mg and 40 mg, were not observed for 6-minute walk distance or pulmonary vascular resistance (PVR) in subjects with PAH in the placebo-controlled study. Median change from baseline in 6-minute walk distance was 32 meters and 35 meters at 16 weeks in subjects receiving 20 mg and 40 mg daily, respectively. Mean change from baseline PVR was -254 dynesseccm-5 and -209 dynesseccm-5 at 16 weeks in patients receiving 20 mg and 40 mg daily, respectively.. 1. 12.3 Pharmacokinetics. Over dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. In PAH patients administered between 20 and 40 mg of tadalafil, an approximately 1.5-fold greater AUC was observed indicating less than proportional increase in exposure over the entire dose range of 2.5 to 40 mg. During tadalafil 20 and 40 mg once daily dosing, steady-state plasma concentrations were attained within days, and exposure was approximately 1.3-fold higher than after single dose.Absorption -- After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between and hours (median time of hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.The rate and extent of absorption of tadalafil is not influenced by food; thus ALYQ(TM) may be taken with or without food.Distribution -- The mean apparent volume of distribution following oral administration is approximately 77 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins.Metabolism -- Tadalafil is predominantly metabolized by CYP3A to 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 suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.Elimination -- Following 40 mg, the mean oral clearance for tadalafil is 3.4 L/hr and the mean terminal half-life is 15 hours in healthy subjects. In patients with pulmonary hypertension not receiving concomitant bosentan, the mean oral clearance for tadalafil is 1.6 L/hr, and the mean terminal half-life is 35 hours. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to lesser extent in the urine (approximately 36% of the dose).Population pharmacokinetics -- In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady-state following 40 mg was 26% higher when compared to those of healthy volunteers. The results suggest lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers.Geriatric patients In healthy male elderly subjects (65 years or over) after 10 mg dose, lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on Cmax was observed relative to that in healthy subjects 19 to 45 years of age.Renal impairmentIn clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment. In subjects with end-stage renal disease on hemodialysis, there was two-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil, respectively. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination [see Dosage and Administration (2.2)].Hepatic impairment In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class or B) was comparable to exposure in healthy subjects when dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (2.3)].Patients with diabetes mellitusIn male patients with diabetes mellitus after 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.Race Pharmacokinetic studies have included subjects from different ethnic groups, and no differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted.Gender In healthy female and male subjects following single and multiple-doses of tadalafil, no clinically relevant differences in exposure (AUC and Cmax) were observed. No dose adjustment is warranted.Drug interaction studiesTadalafil is substrate of and predominantly metabolized by CYP3A. Cytochrome P450 3A4 inhibitorsKetoconazole increased tadalafil exposure relative to the values for tadalafil alone (Figure 2). Although specific interactions have not been studied, other CYP3A inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.RitonavirRitonavir increased tadalafil 20-mg single-dose exposure relative to the values for tadalafil alone. Ritonavir inhibits and induces CYP3A, the enzyme involved in the metabolism of tadalafil, in time-dependent manner. The initial inhibitory effect of ritonavir on CYP3A may be mitigated by more slowly evolving induction effect so that after about week of ritonavir twice daily, the exposure of tadalafil is similar in the presence of and absence of ritonavir [see Dosage and Administration (2.4) and Drug Interactions (7.5)]. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure.Cytochrome P450 3A4 inducersRifampin (600 mg daily), CYP3A inducer, reduced tadalafil 10 mg single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone [see Drug Interactions (7.5)].Bosentan, substrate of CYP2C9 and CYP3A and moderate inducer of CYP3A, CYP2C9 and possibly CYP2C19, reduced tadalafil systemic exposure following multiple-dose co-administration (Figure 2). Although specific interactions have not been studied, other CYP3A inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure.Exposure changes of tadalafil following co-administration with other drugs are shown in Figure 2.Change relative to Tadalafil alonea Ritonavir is also CYP2C9/CYP2C19/CYP2D6 Inhibitor and CYP3A inducer.b [see Dosage and Administration (2.4)].c Bosentan is also CYP2C9/CYP2C19 inducer.Figure 2: Impact of Other Drugs on the Pharmacokinetics of TadalafilCytochrome P450 substrates -- Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms.Exposure changes of drugs following co-administration with tadalafil are shown in Figure 3.Change relative to coadministered drug alonea small augmentation (increase of beats per minute) in heart rate was observed with theophylline.b Tadalafil (40 mg qd) had no clinically significant effect on exposure (AUC and Cmax) of bosentan metabolites.c 95% CIFigure 3: Impact of Tadalafil on the Pharmacokinetics of Other Drugs. 1. 1.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 ALYQ(TM) for Pulmonary Arterial Hypertension. randomized, double-blind, 16 week placebo-controlled study was conducted in 405 patients with pulmonary arterial hypertension, defined as resting mean pulmonary artery pressure (mPAP) >=25 mm Hg, pulmonary capillary wedge pressure (PCWP) <=15 mm Hg, and pulmonary vascular resistance (PVR) >=3 Wood units via right heart catheterization. Allowed background therapy included bosentan (maintenance dosing up to 125 mg twice daily) and chronic anticoagulation. The use of prostacyclin or analogue, L-arginine, phosphodiesterase inhibitor, or other chronic PAH medications were not permitted.Subjects were randomly assigned to of treatment groups (tadalafil 2.5, 10, 20, 40 mg, or placebo) in 1:1:1:1:1 ratio. Subjects had to be at least 12 years of age and had diagnosis of PAH that was idiopathic, heritable, related to connective tissue disease, anorexigen use, human immunodeficiency virus (HIV) infection, associated with an atrial-septal defect, or associated with surgical repair of congenital systemic-to-pulmonary shunt of least year in duration (for example, ventricular septal defect, patent ductus arteriosus). Patients with history of left-sided heart disease, severe renal insufficiency, or pulmonary hypertension related to conditions other than specified in the inclusion criteria were not eligible for enrollment.The mean age of all subjects was 54 years (range 14-90 years) with the majority of subjects being Caucasian (81%) and female (78%). PAH etiologies were predominantly idiopathic or heritable PAH (61%) and related to connective tissue disease (23%). More than half (53%) of the subjects in the study were receiving concomitant bosentan therapy. The majority of subjects had World Health Organization (WHO) Functional Class III (65%) or II (32%). The mean baseline 6-minute walk distance (6-MWD) was 343 meters. Of the 405 subjects, 341 completed the study.The primary efficacy endpoint was the change from baseline at week 16 in 6-MWD (see Figure 4). In the tadalafil 40 mg treatment group, the placebo-adjusted mean change increase in 6-MWD was 33 meters (95% C.I. 15-50 meters; p=0.0004). The improvement in 6-MWD was apparent at weeks of treatment and then maintained at week 12 and week 16. Figure 4: 6-Minute Walk Distance (meters) Mean Change from Baseline, with 95% Confidence IntervalsPlacebo-adjusted changes in 6-MWD at 16 weeks were evaluated in subgroups (see Figure 5). In patients taking only ALYQ(TM) 40 mg (i.e., without concomitant bosentan), the placebo-adjusted mean change in 6-MWD was 44 meters. In patients taking tadalafil 40 mg and concomitant bosentan therapy, the placebo adjusted mean change in 6-MWD was 23 meters.Figure 5: Placebo-adjusted Mean Change in 6-Minute Walk Distance (meters) of ALYQ(TM) 40 mg, with 95% Confidence Intervals There was less clinical worsening (defined as death, lung transplantation, atrial septostomy, hospitalization because of worsening PAH, initiation of new PAH therapy [prostacyclin or analog, endothelin receptor antagonist, PDE5 inhibitor], or worsening WHO functional class) in the ALYQ(TM) 40 mg group compared to the placebo group and the groups that used lower doses of ALYQ(TM).Table 2: Number (percent) with Clinical Worsening TadalafilPlacebo2.5 mg10 mg20 mg40 mgN=82N=82 N=80 N=82 N=79 Total with clinical worsening 13 (16) 10 (12) (9) (10) (5) Death 0 0 Hospitalization for worsening PAH 2 0 New PAH therapy 1 2 Worsening WHO class 11 10 63 Subjects may be counted in more than one categoryThe Kaplan-Meier plot of times to clinical worsening is shown below in Figure 6.Figure 6: Kaplan-Meier Plot of Time to Clinical Worsening. 1. 1. figure3. 14.2 Long-Term Treatment of Pulmonary Arterial Hypertension. Patients (N=357) from the placebo-controlled study entered long-term extension study. Of these, 311 patients have been treated with tadalafil for at least months and 182 for year (median exposure 356 days; range days to 415 days). The survival rate in the extension study was 96.5 per 100 patient years. Without control group, these data must be interpreted cautiously.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Concomitant organic nitrates (4.1)Concomitant Guanylate Cyclase (GC) Stimulators (4.2)History of known serious hypersensitivity reaction to ALYQ(TM) or CIALIS(R) (4.3). Concomitant organic nitrates (4.1). Concomitant Guanylate Cyclase (GC) Stimulators (4.2). History of known serious hypersensitivity reaction to ALYQ(TM) or CIALIS(R) (4.3). 4.1 Concomitant Organic Nitrates. ALYQ(TM) is contraindicated in patients who are using any form of organic nitrate, either regularly or intermittently. Do not use nitrates within 48 hours of the last dose of ALYQ(TM). ALYQ(TM) potentiates the hypotensive effect of nitrates. This potentiation is thought to result from the combined effects of nitrates and ALYQ(TM) on the nitric oxide/cGMP pathway [see Clinical Pharmacology (12.2)].. 4.2 Concomitant Guanylate Cyclase (GC) Stimulators. Coadministration of GC stimulators, such as riociguat with ALYQ(TM) is contraindicated. ALYQ(TM) may potentiate the hypotensive effects of GC stimulators.. 4.3 Hypersensitivity Reactions. ALYQ(TM) is contraindicated in patients with known serious hypersensitivity to tadalafil (ALYQ(TM) or CIALIS(R)). Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions (6.2)].

DESCRIPTION SECTION.

11 DESCRIPTION. ALYQ(TM) (tadalafil, USP), an oral treatment for pulmonary arterial hypertension, is selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type (PDE5). The structural formula is:C22H19N3O4 M.W. 389.41 The chemical designation is pyrazino[1,2:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R-12aR). It is white to off-white crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.ALYQ(TM) is available as orange, film-coated, oval-shaped tablets for oral administration. Each tablet contains 20 mg of tadalafil, USP and the following inactive ingredients: croscarmellose sodium, iron oxide red, iron oxide yellow, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-part hydrolyzed, povidone, sodium lauryl sulfate, sodium starch glycolate, sodium stearyl fumarate, talc, and titanium dioxide.. 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 40 mg once daily, with or without food. (2.1)Dividing the dose (40 mg) over the course of the day is not recommended. (2.1)Use with ritonavir requires dosage adjustments. (2.4). 40 mg once daily, with or without food. (2.1). Dividing the dose (40 mg) over the course of the day is not recommended. (2.1). Use with ritonavir requires dosage adjustments. (2.4). 2.1 Pulmonary Arterial Hypertension. The recommended dose of ALYQ(TM) is 40 mg (two 20 mg tablets) taken once daily with or without food. Dividing the dose (40 mg) over the course of the day is not recommended.. 2.2 Dose Adjustment in Renal Impairment. Mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min): Start dosing at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.Severe (creatinine clearance <30 mL/min and on hemodialysis): Avoid use of ALYQ(TM) because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Use in Specific Populations (8.6)]. 2.3 Dose Adjustment in Hepatic Impairment. Mild or moderate (Child Pugh Class or B): Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis, consider starting dose of 20 mg once per day.Severe (Child Pugh Class C): Patients with severe hepatic cirrhosis have not been studied. Avoid use of ALYQ(TM) [see Use in Specific Populations (8.7)]. 2.4 Dose Adjustments for Use withRitonavir. Co-administration of ALYQ(TM) in Patients on RitonavirIn patients receiving ritonavir for at least one week, start ALYQ(TM) at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].Co-administration of Ritonavir in Patients on ALYQ(TM) Avoid use of ALYQ(TM) during the initiation of ritonavir. Stop ALYQ(TM) at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ALYQ(TM) at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 20 mg, orange, oval-shaped, film-coated tablets (not scored) debossed with TEVA on one side and with 3334 on the other side.. Tablets (not scored): 20 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Nitrates. Administration of nitrates within 48 hours after the last dose of ALYQ(TM) is contraindicated [see Contraindications (4.1)].. 7.2 Alpha-Blockers. PDE5 inhibitors, including ALYQ(TM), 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. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, alfuzosin or tamsulosin [see Clinical Pharmacology (12.2)].. 7.3 Antihypertensives. PDE5 inhibitors, including ALYQ(TM), are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood-pressure-lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo [see Clinical Pharmacology (12.2)].. 7.4 Alcohol. Both alcohol and tadalafil, PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., units or greater) in combination with ALYQ(TM) can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil (10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. [see Clinical Pharmacology (12.2)]. 7.5 CYP3A Inhibitors/Inducers. RitonavirRitonavir initially inhibits and later induces CYP3A, the enzyme involved in the metabolism of tadalafil. At steady state of ritonavir (about week), the exposure to tadalafil is similar as in the absence of ritonavir [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].Potent Inhibitors of CYP3ATadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole, and itraconazole, avoid use of ALYQ(TM) [see Clinical Pharmacology (12.3)].Potent Inducers of CYP3A For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of ALYQ(TM) [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of subjects in the clinical study of tadalafil for pulmonary arterial hypertension, 28 percent were 65 and over, while 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, greater sensitivity to medications in some older individuals should be considered. [See Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. ALYQ(TM) (tadalafil tablets USP) is supplied as follows:20 mg orange, oval-shaped, film-coated tablets (not scored), debossed with TEVA on one side and with 3334 on the other side of the tablet in bottles of 60 (NDC 0093-3334-06).. 16.2 Storage. Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature]. Keep out of reach of children.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ALYQ(TM) is phosphodiesterase (PDE5) inhibitor 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%). (1.1). 1.1 Pulmonary Arterial Hypertension. ALYQ(TM) is 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%).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling (Patient Information)Inform patients of contraindication of ALYQ(TM) with any use of organic nitrates or GC stimulators.Inform patients that tadalafil is also marketed as CIALIS(R) for erectile dysfunction (ED) and for the signs and symptoms of benign prostatic hyperplasia (BPH). Advise patients taking ALYQ(TM) not to take CIALIS(R) or other PDE5 inhibitors. Advise patients to seek immediate medical attention in the event of sudden loss of vision in one or both eyes while taking ALYQ(TM). Such an event may be sign of NAION. Also discuss with patients that there is an 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.Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking ALYQ(TM). These events may be accompanied by tinnitus and dizziness.Brands listed are the trademarks of their respective owners.Manufactured In Israel By: Teva Pharmaceutical Ind. Ltd. Jerusalem, 9777402, Israel Manufactured For: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454Rev. 9/2021. Inform patients of contraindication of ALYQ(TM) with any use of organic nitrates or GC stimulators.. Inform patients that tadalafil is also marketed as CIALIS(R) for erectile dysfunction (ED) and for the signs and symptoms of benign prostatic hyperplasia (BPH). Advise patients taking ALYQ(TM) not to take CIALIS(R) or other PDE5 inhibitors. Advise patients to seek immediate medical attention in the event of sudden loss of vision in one or both eyes while taking ALYQ(TM). Such an event may be sign of NAION. Also discuss with patients that there is an 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.. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking ALYQ(TM). These events may be accompanied by tinnitus and dizziness.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Tadalafil is an inhibitor of phosphodiesterase type (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.Studies in vitro have demonstrated that tadalafil is selective inhibitor of PDE5. PDE5 is found in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is 10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is 9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, tadalafil inhibits human recombinant PDE11A1 and, to lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis -- Tadalafil was not carcinogenic to rats or mice when administered daily for 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.Mutagenesis -- 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, 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 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 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 years. 13.2 Animal Toxicology and/or Pharmacology. Animal studies showed vascular inflammation in tadalafil-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 1- to 17-fold the human exposure (AUCs) at the MRHD of 40 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1- and 6-month studies at unbound tadalafil exposure of 0.5- to 38-fold the human exposure (AUC) at the MRHD of 40 mg. In 12-month dog study, no disseminated arteritis was observed, but dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 4- to 10-fold the human exposure at the MRHD of 40 mg. The abnormal blood-cell findings were reversible within weeks upon removal of the drug.

NURSING MOTHERS SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of tadalafil and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-times that found in the plasma. When drug is present in animal milk, it is likely that the drug will be present in human milk.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ALYQ(TM) and any potential adverse effects on the breastfed child from ALYQ(TM) or from the underlying maternal condition.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Single doses up to 500 mg have been given to healthy male subjects, and multiple daily doses up to 100 mg have been given to male patients with erectile dysfunction. Adverse reactions were similar to those seen at lower doses. Doses greater than 40 mg have not been studied in patients with pulmonary arterial hypertension. In cases of overdose, standard supportive measures should be adopted as needed. Hemodialysis contributes negligibly to tadalafil elimination.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 0093-3334-06ALYQTM (tadalafil tablets USP)20 mgRx only60 TABLETS pdp label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of ALYQ(TM) in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Effects on Blood Pressure When Administered with NitratesIn clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Do not use ALYQ(TM) in patients taking any form of nitrates [see Contraindications (4.1)].A double-blind, placebo-controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) assessed the interaction between nitroglycerin and tadalafil. Subjects received daily doses of tadalafil 20 mg or matching placebo for days and then were given single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified timepoints following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although few more tadalafil subjects compared to placebo experienced greater blood-pressure lowering effects at this timepoint. After 48 hours, the interaction was not detectable [See Contraindications (4.1)]. Effects on Blood Pressure.The effects of tadalafil on blood pressure alone and administered with antihypertensives, alcohol, and alpha-blockers is shown in Figure 1.a In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed, and dizziness occurred at similar frequency to alcohol alone.b In studies of tadalafil co-administration with doxazosin, the number of subjects with potentially clinically significant standing blood pressure decreases was greater for the combination. Some patients had symptoms associated with the decrease in blood pressure including syncope.Figure 1: Effects of Tadalafil on Blood PressureEffects on Cardiac ElectrophysiologyThe effect of single 100 mg dose of tadalafil (2.5 times the recommended dose) on the QT interval was evaluated at the time of peak tadalafil concentration in randomized, double-blinded, placebo, and active-controlled (intravenous ibutilide) crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). In this study, the mean increase in heart rate associated with 100 mg dose of tadalafil compared to placebo was 3.1 beats per minute. Effects on Exercise Stress TestingThe effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was similar to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates.Effects on VisionSingle oral doses of PDE inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In study to assess the effects of single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (<0.1% of patients).Effects on Sperm CharacteristicsThree studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for months and the study of 20 mg tadalafil for months, results showed decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.Dose-Response RelationshipDose-response relationships, between 20 mg and 40 mg, were not observed for 6-minute walk distance or pulmonary vascular resistance (PVR) in subjects with PAH in the placebo-controlled study. Median change from baseline in 6-minute walk distance was 32 meters and 35 meters at 16 weeks in subjects receiving 20 mg and 40 mg daily, respectively. Mean change from baseline PVR was -254 dynesseccm-5 and -209 dynesseccm-5 at 16 weeks in patients receiving 20 mg and 40 mg daily, respectively.. 1.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Over dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. In PAH patients administered between 20 and 40 mg of tadalafil, an approximately 1.5-fold greater AUC was observed indicating less than proportional increase in exposure over the entire dose range of 2.5 to 40 mg. During tadalafil 20 and 40 mg once daily dosing, steady-state plasma concentrations were attained within days, and exposure was approximately 1.3-fold higher than after single dose.Absorption -- After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between and hours (median time of hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.The rate and extent of absorption of tadalafil is not influenced by food; thus ALYQ(TM) may be taken with or without food.Distribution -- The mean apparent volume of distribution following oral administration is approximately 77 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins.Metabolism -- Tadalafil is predominantly metabolized by CYP3A to 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 suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.Elimination -- Following 40 mg, the mean oral clearance for tadalafil is 3.4 L/hr and the mean terminal half-life is 15 hours in healthy subjects. In patients with pulmonary hypertension not receiving concomitant bosentan, the mean oral clearance for tadalafil is 1.6 L/hr, and the mean terminal half-life is 35 hours. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to lesser extent in the urine (approximately 36% of the dose).Population pharmacokinetics -- In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady-state following 40 mg was 26% higher when compared to those of healthy volunteers. The results suggest lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers.Geriatric patients In healthy male elderly subjects (65 years or over) after 10 mg dose, lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on Cmax was observed relative to that in healthy subjects 19 to 45 years of age.Renal impairmentIn clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment. In subjects with end-stage renal disease on hemodialysis, there was two-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil, respectively. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination [see Dosage and Administration (2.2)].Hepatic impairment In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class or B) was comparable to exposure in healthy subjects when dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (2.3)].Patients with diabetes mellitusIn male patients with diabetes mellitus after 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.Race Pharmacokinetic studies have included subjects from different ethnic groups, and no differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted.Gender In healthy female and male subjects following single and multiple-doses of tadalafil, no clinically relevant differences in exposure (AUC and Cmax) were observed. No dose adjustment is warranted.Drug interaction studiesTadalafil is substrate of and predominantly metabolized by CYP3A. Cytochrome P450 3A4 inhibitorsKetoconazole increased tadalafil exposure relative to the values for tadalafil alone (Figure 2). Although specific interactions have not been studied, other CYP3A inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.RitonavirRitonavir increased tadalafil 20-mg single-dose exposure relative to the values for tadalafil alone. Ritonavir inhibits and induces CYP3A, the enzyme involved in the metabolism of tadalafil, in time-dependent manner. The initial inhibitory effect of ritonavir on CYP3A may be mitigated by more slowly evolving induction effect so that after about week of ritonavir twice daily, the exposure of tadalafil is similar in the presence of and absence of ritonavir [see Dosage and Administration (2.4) and Drug Interactions (7.5)]. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure.Cytochrome P450 3A4 inducersRifampin (600 mg daily), CYP3A inducer, reduced tadalafil 10 mg single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone [see Drug Interactions (7.5)].Bosentan, substrate of CYP2C9 and CYP3A and moderate inducer of CYP3A, CYP2C9 and possibly CYP2C19, reduced tadalafil systemic exposure following multiple-dose co-administration (Figure 2). Although specific interactions have not been studied, other CYP3A inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure.Exposure changes of tadalafil following co-administration with other drugs are shown in Figure 2.Change relative to Tadalafil alonea Ritonavir is also CYP2C9/CYP2C19/CYP2D6 Inhibitor and CYP3A inducer.b [see Dosage and Administration (2.4)].c Bosentan is also CYP2C9/CYP2C19 inducer.Figure 2: Impact of Other Drugs on the Pharmacokinetics of TadalafilCytochrome P450 substrates -- Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms.Exposure changes of drugs following co-administration with tadalafil are shown in Figure 3.Change relative to coadministered drug alonea small augmentation (increase of beats per minute) in heart rate was observed with theophylline.b Tadalafil (40 mg qd) had no clinically significant effect on exposure (AUC and Cmax) of bosentan metabolites.c 95% CIFigure 3: Impact of Tadalafil on the Pharmacokinetics of Other Drugs. 1. 1.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLimited data from case series with tadalafil use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day based on AUC (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.DataAnimal DataTadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.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 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis based on AUC. In one of two perinatal/postnatal developmental studies in rats, reduction of postnatal pup survival was observed at dose levels of 60, 200 and 1000 mg/kg. The no-observed effect- level (NOEL) for developmental toxicity was 30 mg/kg, which provided maternal exposure to unbound tadalafil concentrations approximately times the exposure at the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 200 mg/kg/day, which produced AUCs greater than times the exposure at the MRHD. Surviving offspring had normal development and reproductive performance.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. ALYQ(TM) (ah-LIQ)(tadalafil) tabletsRead this patient information before you start taking ALYQ(TM) and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.What is the most important information should know about ALYQ(TM)Never take ALYQ(TM) with any nitrate or guanylate cyclase stimulator medicines:Your blood pressure could drop quickly to an unsafe levelYou could get dizzy, faint and even have heart attack or stroke.Nitrates include:Medicines that treat chest pain (angina)Nitroglycerin in any form including tablets, patches, sprays, and ointmentsOther nitrate medicines (isosorbide mononitrate or dinitrate)Street drugs that are inhaled, called poppers (amyl nitrate, butyl nitrate or nitrite) Guanylate cyclase stimulators include:Riociguat (Adempas(R)) medicine that treats pulmonary arterial hypertension and chronic-thromboembolic pulmonary hypertensionAsk your healthcare provider or pharmacist if you are not sure if you take nitrate or guanylate cyclase stimulator medicine.What is ALYQ(TM)ALYQ(TM) is prescription medicine used to treat pulmonary arterial hypertension (PAH, high blood pressure in your lungs) to improve your ability to exercise.It is not known if ALYQ(TM) is safe or effective in children.Who should not take ALYQ(TM) Do not take ALYQ(TM) if youtake any medicines called nitrates.use recreational drugs called poppers like amyl nitrate, butyl nitrate or nitrite.take any medicines called guanylate cyclase stimulatorsare allergic to tadalafil or any other ingredient in ALYQ(TM). See What are the ingredients in ALYQ(TM) at the end of this leaflet.See What is the most important information should know about ALYQ(TM) What should tell my healthcare provider before taking ALYQ(TM)Before taking ALYQ(TM), tell your healthcare provider about all of your medical conditions, including if you:are allergic to ALYQ(TM) or CIALIS(R) or any of its ingredients. See the end of this leaflet for complete list of ingredients in ALYQ(TM).have pulmonary veno-occlusive disease (PVOD)have heart problems have low blood pressure have liver problemshave kidney problems or get dialysishave retinitis pigmentosa, rare genetic eye diseasehave ever had any sudden vision loss, including any damage to your optic nerve or NAION.have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearinghave deformed penis shape or Peyronies diseasehave had an erection that lasted more than hourshave blood cell problems such as sickle cell anemia, multiple myeloma, or leukemiaare pregnant or planning to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant.are breastfeeding or plan to breast feed. If you breastfeed while taking ALYQ(TM), it is likely that ALYQ(TM) will pass into your breast milk. You and your healthcare provider should decide if you will take ALYQ(TM) or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. ALYQ(TM) and other medicines may affect each other.Especially tell your healthcare provider if you take any of these medicines:nitrates or guanylate cyclase stimulators (see What is the most important information should know about ALYQ(TM))alpha blockers, used to treat prostate disease and high blood pressure. Your blood pressure could suddenly drop. You could get dizzy or faint.protease inhibitors, used to treat HIV infection, such as ritonavir (Norvir(R), Kaletra(R))ketoconazole (Extina(R), Xolegel(R), Ketozole(R), Nizoral A-D(R), Nizoral(R)) itraconazole (Sporanox(R))erythromycin (several brand names exist. Please consult your healthcare provider to determine if you are taking this medicine)rifampin (Rifadin(R), Rifamate(R), Rifater(R), Rimactane(R))bosentan (Tracleer(R))phenobarbital, phenytoin (Dilantin(R)), carbamazepine (Tegretol(R))CIALIS(R) or other medicines or treatments for erectile dysfunction (impotence).Tadalafil is also marketed as CIALIS(R) for the treatment of male erectile dysfunction (ED, impotence) and for the signs and symptoms of benign prostatic hyperplasia (BPH, enlarged prostate). Do not take both ALYQ(TM) and CIALIS(R). Do not take ALYQ(TM) and other medicines or treatments for erectile dysfunction.Ask your healthcare provider or pharmacist for list of these medicines, if you are not sure. Know the medicines you take. Keep list of them and show it to your healthcare provider and pharmacist when you get new medicine.How should take ALYQ(TM)Take ALYQ(TM) exactly as your healthcare provider tells you.Take ALYQ(TM) tablets at the same time every day. You should take both tablets at the same time, one after the other, every day. Do not split your dose.ALYQ(TM) can be taken with or without food.Do not change your dose or stop taking ALYQ(TM) without speaking to your healthcare provider.If you take too much ALYQ(TM), call your healthcare provider or go to an emergency department right away.What should avoid while taking ALYQ(TM)Do not have more than alcohol-containing drinks in short period of time while you take ALYQ(TM). Drinking too much alcohol can lower your blood pressure. You could get dizzy or faint.What are the possible side effects of ALYQ(TM)The following side effects were reported rarely in patients taking tadalafil:Decreased eyesight or loss of vision in one or both eyes (NAION). If you notice sudden decrease or loss of vision in one or both eyes, contact healthcare provider right away.Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice sudden decrease or loss of hearing, contact healthcare provider right away.In men, an erection that lasts more than hours (with or without pain). Talk to your healthcare provider or go to the emergency department right away. An erection that lasts more than hours must be treated as soon as possible or you can have lasting damage to your penis, including the inability to have erections.See What is the most important information should know about ALYQ(TM) The most common side effects with ALYQ(TM) include:headachemuscle paingetting red or hot in the face (flushing)nauseapain in the arms, legs, or backupset stomachstuffy or congested nose Tell your healthcare provider about any side effect that bothers you or does not go away.These are not all the possible side effects of ALYQ(TM). For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How Should Store ALYQ(TM)Store ALYQ(TM) tablets at room temperature between 68 to 77F (20 to 25C).Keep ALYQ(TM) and all medicines out of the reach of children.General Information about the safe and effective use of ALYQ(TM)Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ALYQ(TM) for condition for which it was not prescribed. Do not give ALYQ(TM) to other people, even if they have the same symptoms you have. It may harm them.This patient information leaflet summarizes the most important information about ALYQ(TM). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ALYQ(TM) that is written for healthcare professionals. For more information, call Teva Pharmaceuticals USA, Inc. at 1-888-838-2872.What are the ingredients in ALYQ(TM)Active Ingredient: tadalafilInactive Ingredients: croscarmellose sodium, iron oxide red, iron oxide yellow, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-part hydrolyzed, povidone, sodium lauryl sulfate, sodium starch glycolate, sodium stearyl fumarate, talc, and titanium dioxide.Rx onlyBrands listed are the trademarks of their respective owners.Manufactured In Israel By: Teva Pharmaceutical Ind. Ltd. Jerusalem, 9777402, Israel Manufactured For: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454Rev. 9/2021 Your blood pressure could drop quickly to an unsafe level. You could get dizzy, faint and even have heart attack or stroke.. Medicines that treat chest pain (angina). Nitroglycerin in any form including tablets, patches, sprays, and ointments. Other nitrate medicines (isosorbide mononitrate or dinitrate). Street drugs that are inhaled, called poppers (amyl nitrate, butyl nitrate or nitrite) Riociguat (Adempas(R)) medicine that treats pulmonary arterial hypertension and chronic-thromboembolic pulmonary hypertension. take any medicines called nitrates.. use recreational drugs called poppers like amyl nitrate, butyl nitrate or nitrite.. take any medicines called guanylate cyclase stimulators. are allergic to tadalafil or any other ingredient in ALYQ(TM). See What are the ingredients in ALYQ(TM) at the end of this leaflet.. are allergic to ALYQ(TM) or CIALIS(R) or any of its ingredients. See the end of this leaflet for complete list of ingredients in ALYQ(TM).. have pulmonary veno-occlusive disease (PVOD). have heart problems have low blood pressure have liver problems. have kidney problems or get dialysis. have retinitis pigmentosa, rare genetic eye disease. have ever had any sudden vision loss, including any damage to your optic nerve or NAION.. have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearing. have deformed penis shape or Peyronies disease. have had an erection that lasted more than hours. have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia. are pregnant or planning to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant.. are breastfeeding or plan to breast feed. If you breastfeed while taking ALYQ(TM), it is likely that ALYQ(TM) will pass into your breast milk. You and your healthcare provider should decide if you will take ALYQ(TM) or breastfeed. You should not do both.. nitrates or guanylate cyclase stimulators (see What is the most important information should know about ALYQ(TM)). alpha blockers, used to treat prostate disease and high blood pressure. Your blood pressure could suddenly drop. You could get dizzy or faint.. protease inhibitors, used to treat HIV infection, such as ritonavir (Norvir(R), Kaletra(R)). ketoconazole (Extina(R), Xolegel(R), Ketozole(R), Nizoral A-D(R), Nizoral(R)) itraconazole (Sporanox(R)). erythromycin (several brand names exist. Please consult your healthcare provider to determine if you are taking this medicine). rifampin (Rifadin(R), Rifamate(R), Rifater(R), Rimactane(R)). bosentan (Tracleer(R)). phenobarbital, phenytoin (Dilantin(R)), carbamazepine (Tegretol(R)). CIALIS(R) or other medicines or treatments for erectile dysfunction (impotence).. Tadalafil is also marketed as CIALIS(R) for the treatment of male erectile dysfunction (ED, impotence) and for the signs and symptoms of benign prostatic hyperplasia (BPH, enlarged prostate). Do not take both ALYQ(TM) and CIALIS(R). Do not take ALYQ(TM) and other medicines or treatments for erectile dysfunction.. Take ALYQ(TM) exactly as your healthcare provider tells you.. Take ALYQ(TM) tablets at the same time every day. You should take both tablets at the same time, one after the other, every day. Do not split your dose.. ALYQ(TM) can be taken with or without food.. Do not change your dose or stop taking ALYQ(TM) without speaking to your healthcare provider.. If you take too much ALYQ(TM), call your healthcare provider or go to an emergency department right away.. Decreased eyesight or loss of vision in one or both eyes (NAION). If you notice sudden decrease or loss of vision in one or both eyes, contact healthcare provider right away.. Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice sudden decrease or loss of hearing, contact healthcare provider right away.. In men, an erection that lasts more than hours (with or without pain). Talk to your healthcare provider or go to the emergency department right away. An erection that lasts more than hours must be treated as soon as possible or you can have lasting damage to your penis, including the inability to have erections.. headache. muscle pain. getting red or hot in the face (flushing). nausea. pain in the arms, legs, or back. upset stomach. stuffy or congested nose.

SPL UNCLASSIFIED SECTION.

1.1 Pulmonary Arterial Hypertension. ALYQ(TM) is 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%).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Renal Impairment (2.2, 8.6, 12.3)Mild or moderate: Start with 20 mg once daily. (2.2, 8.6)Severe: Avoid use of ALYQ(TM). (2.2, 8.6)Hepatic Impairment (2.2, 8.7, 12.3) Mild or moderate: Consider starting dose of 20 mg once daily. (2.3, 8.7)Severe: Avoid use of ALYQ(TM). (2.3, 8.7). Mild or moderate: Start with 20 mg once daily. (2.2, 8.6). Severe: Avoid use of ALYQ(TM). (2.2, 8.6). Mild or moderate: Consider starting dose of 20 mg once daily. (2.3, 8.7). Severe: Avoid use of ALYQ(TM). (2.3, 8.7). 8.1 Pregnancy. Risk SummaryLimited data from case series with tadalafil use in pregnant women have not identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day based on AUC (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.DataAnimal DataTadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.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 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis based on AUC. In one of two perinatal/postnatal developmental studies in rats, reduction of postnatal pup survival was observed at dose levels of 60, 200 and 1000 mg/kg. The no-observed effect- level (NOEL) for developmental toxicity was 30 mg/kg, which provided maternal exposure to unbound tadalafil concentrations approximately times the exposure at the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 200 mg/kg/day, which produced AUCs greater than times the exposure at the MRHD. Surviving offspring had normal development and reproductive performance.. 8.2 Lactation. Risk SummaryThere are no data on the presence of tadalafil and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-times that found in the plasma. When drug is present in animal milk, it is likely that the drug will be present in human milk.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ALYQ(TM) and any potential adverse effects on the breastfed child from ALYQ(TM) or from the underlying maternal condition. 8.3Females and Males of Reproductive Potential. InfertilityMalesBased on the data from studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for months and the study of 20 mg tadalafil for months. This effect was not seen in the study of 20 mg tadalafil taken for 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. There have been no studies evaluating the effect of tadalafil on fertility in men or women [see Clinical Pharmacology (12.2)].. 8.4 Pediatric Use. Safety and effectiveness of ALYQ(TM) in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number of subjects in the clinical study of tadalafil for pulmonary arterial hypertension, 28 percent were 65 and over, while 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, greater sensitivity to medications in some older individuals should be considered. [See Clinical Pharmacology (12.3)].. 8.6 Renal Impairment. For patients with mild or moderate renal impairment, start ALYQ(TM) at 20 mg once daily. Increase the dose to 40 mg once daily based upon individual tolerability [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].In patients with severe renal impairment, avoid use of ALYQ(TM) because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment. Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class or B), consider starting dose of ALYQ(TM) 20 mg once daily. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, thus avoid use of ALYQ(TM) in such patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypotension: Carefully consider whether patients with certain underlying cardiovascular disease could be adversely affected by vasodilatory effects of ALYQ(TM). Not recommended in patients with pulmonary veno-occlusive disease. (5.1, 5.2)Effects on the eye: Sudden loss of vision could be sign of non-arteritic ischemic optic neuropathy (NAION) and may be permanent. (5.3)Hearing impairment: Cases of sudden decrease or loss of hearing have been reported with CIALIS(R). (5.4)Concomitant PDE5 inhibitors: Avoid use with CIALIS(R) or other PDE5 inhibitors. (5.5)Prolonged erection: Advise patients to seek emergency treatment if an erection lasts >4 hours. (5.6). Hypotension: Carefully consider whether patients with certain underlying cardiovascular disease could be adversely affected by vasodilatory effects of ALYQ(TM). Not recommended in patients with pulmonary veno-occlusive disease. (5.1, 5.2). Effects on the eye: Sudden loss of vision could be sign of non-arteritic ischemic optic neuropathy (NAION) and may be permanent. (5.3). Hearing impairment: Cases of sudden decrease or loss of hearing have been reported with CIALIS(R). (5.4). Concomitant PDE5 inhibitors: Avoid use with CIALIS(R) or other PDE5 inhibitors. (5.5). Prolonged erection: Advise patients to seek emergency treatment if an erection lasts >4 hours. (5.6). 5.1 Hypotension. ALYQ(TM) has vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing ALYQ(TM), carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with preexisting hypotension, with autonomic dysfunction, with left ventricular outflow obstruction, may be particularly sensitive to the actions of vasodilators. 5.2 Worsening Pulmonary Vascular Occlusive Disease. 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 ALYQ(TM) to patients with veno-occlusive disease, administration of ALYQ(TM) to such patients is not recommended. Should signs of pulmonary edema occur when ALYQ(TM) is administered, the possibility of associated PVOD should be considered. 5.3 Visual Loss. When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type (PDE-5) inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (crowded disc), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged >=50 in the general population. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as class, typical of erectile dysfunction treatment, occurred immediately before NAION onset (within half-lives), compared to PDE5 inhibitor use in prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with risk estimate of 2.15 (95% CI 1.06, 4.34). similar study reported consistent result, with 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. 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. 5.4 Hearing Impairment. Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in patients taking tadalafil. 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 (6.2)].. 5.5 Combination withOther PDE5 Inhibitors. Tadalafil is also marketed for erectile dysfunction. The safety and efficacy of taking ALYQ(TM) together with another PDE5 inhibitor has not been studied. Inform patients taking ALYQ(TM) not to take other PDE5 inhibitors.. 5.6 Prolonged Erection. There have been reports of prolonged erections greater than hours and priapism (painful erections greater than hours in duration) for this class of compounds. Patients with 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 Peyronies disease) are at an increased risk. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than hours, whether painful or not, should seek emergency medical attention.