TADLIQ

TADLIQ contains tadalafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C 22 H 19 N 3 O 4 representing a molecular weight of 389.41. The structural formula is: 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 a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol. TADLIQ oral suspension contains 20 mg/5 mL of tadalafil and the following inactive ingredients: 30% simethicone emulsion, citric acid monohydrate, glycerin, peppermint flavor, polysorbate 80, purified water, sodium benzoate, sucralose, trisodium citrate dihydrate, xanthan gum. Structural Formula

TADLIQ is a phosphodiesterase 5 (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 TADLIQ ® 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%).

40 mg (10 mL) once daily, with or without food. ( 2.1 ) Use with ritonavir requires dosage adjustments. ( 2.4 ) 2.1 Pulmonary Arterial Hypertension The recommended dose of TADLIQ is 40 mg (10 mL) taken once daily with or without food. 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 (5mL) once daily. Increase to 40 mg (10 mL) once daily based on individual tolerability. Severe (creatinine clearance <30 mL/min and on hemodialysis): Avoid use of TADLIQ 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 A or B): Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis, consider a starting dose of 20 mg (5 mL) once per day. Severe (Child Pugh Class C): Patients with severe hepatic cirrhosis have not been studied. Avoid use of TADLIQ [see Use in Specific Populations ( 8.7 )] . 2.4 Dose Adjustment for Use with Ritonavir Co-administration of TADLIQ in Patients on Ritonavir In patients receiving ritonavir for at least one week, start TADLIQ at 20 mg (5 mL) once daily. Increase to 40 mg (10 mL) once daily based upon individual tolerability [see Drug Interactions ( 7.5 ) and Clinical Pharmacology ( 12.3 )] . Co-administration of Ritonavir in Patients on TADLIQ Avoid use of TADLIQ during the initiation of ritonavir. Stop TADLIQ at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume TADLIQ at 20 mg (5 mL) once daily. Increase to 40 mg (10 mL) once daily based upon individual tolerability [see Drug Interactions ( 7.5 ) and Clinical Pharmacology ( 12.3 )] .

Concomitant organic nitrates ( 4.1 ) Concomitant Guanylate Cyclase (GC) Stimulators ( 4.2 ) History of known serious hypersensitivity reaction to TADLIQ, ADCIRCA ® or CIALIS ® ( 4.3 ) 4.1 Concomitant Organic Nitrates TADLIQ 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 TADLIQ. TADLIQ potentiates the hypotensive effect of nitrates. This potentiation is thought to result from the combined effects of nitrates and TADLIQ 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 TADLIQ is contraindicated. TADLIQ may potentiate the hypotensive effects of GC stimulators. 4.3 Hypersensitivity Reactions TADLIQ is contraindicated in patients with a known serious hypersensitivity to tadalafil (TADLIQ, ADCIRCA ® or CIALIS ® ). Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions ( 6.2 )] .

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 )] 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 CMP Development, LLC at 1-844-321-1443, 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 a 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 tadalafil, a 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 tadalafil 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 tadalafil 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 1 presents treatment-emergent adverse events reported by ≥9% of patients in the tadalafil 40 mg group and occurring more frequently than with placebo. Table 1: Treatment-Emergent Adverse Events Reported by ≥9% of Patients in Tadalafil and More Frequent than Placebo by 2% EVENT Placebo (%) (N=82) Tadalafil 20 mg (%) (N=82) Tadalafil 40 mg (%) (N=79) Headache 15 32 42 Myalgia 4 9 14 Nasopharyngitis 7 2 13 Flushing 2 6 13 Respiratory Tract Infection (Upper and Lower) 6 7 13 Pain in Extremity 2 5 11 Nausea 6 10 11 Back Pain 6 12 10 Dyspepsia 2 13 10 Nasal Congestion (Including sinus congestion) 1 0 9 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 a combination of these factors. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a 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 a 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 patient's underlying cardiovascular disease, to a combination of these factors, or to other factors. Body as a whole — Hypersensitivity reactions including urticaria, Stevens–Johnson syndrome, and exfoliative dermatitis Nervous — Migraine, seizure and seizure recurrence, and transient global amnesia Ophthalmologic — Visual field defect, retinal vein occlusion, retinal artery occlusion, and NAION [see Warnings and Precautions ( 5.3 )]. 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 a 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 patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions ( 5.4 )] . Urogenital — Priapism [see Warnings and Precautions ( 5.6 )] .

7.1 Nitrates Administration of nitrates within 48 hours after the last dose of TADLIQ is contraindicated [see Contraindications ( 4.1 )] . 7.2 Alpha-Blockers PDE5 inhibitors, including TADLIQ, 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 TADLIQ, 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, a 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., 5 units or greater) in combination with TADLIQ 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 Ritonavir Ritonavir initially inhibits and later induces CYP3A, the enzyme involved in the metabolism of tadalafil. At steady state of ritonavir (about 1 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 CYP3A Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole, and itraconazole, avoid use of TADLIQ [see Clinical Pharmacology ( 12.3 )] . Potent Inducers of CYP3A For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of TADLIQ [see Clinical Pharmacology ( 12.3 )] .

16.2 Storage Store at 20°C to 25°C (68°F to 77°F): excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Shake well for 30 seconds before use. Dispense in a tight container as defined in the USP. Keep out of reach of children.