TADLIQ

TADLIQ- tadalafil suspension
CMP Pharma, Inc.

1 INDICATIONS AND USAGE

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%).

2 DOSAGE AND ADMINISTRATION

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 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 Adjustments 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)].

3 DOSAGE FORMS AND STRENGTHS

Oral Suspension: 20 mg/5 mL; white to off-white opaque suspension with a peppermint flavor.

4 CONTRAINDICATIONS

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)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypotension

TADLIQ has vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing TADLIQ, 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 TADLIQ to patients with veno-occlusive disease, administration of TADLIQ to such patients is not recommended. Should signs of pulmonary edema occur when TADLIQ 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), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (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 a class, typical of erectile dysfunction treatment, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate doubling in the risk of NAION. 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 with Other PDE5 Inhibitors

Tadalafil is also marketed for erectile dysfunction. The safety and efficacy of taking TADLIQ together with another PDE5 inhibitor has not been studied. Inform patients taking TADLIQ not to take other PDE5 inhibitors.

5.6 Prolonged Erection

There have been reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 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 Peyronie’s 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 4 hours, whether painful or not, should seek emergency medical attention.

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)]
• Hearing loss [see Warnings and Precautions (5.4)]
• Priapism [see Warnings and Precautions (5.6)]

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