Tadliq
(tadalafil)Dosage & Administration
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Tadliq Prescribing Information
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%).
Pulmonary Arterial Hypertension
The recommended dose of TADLIQ is 40 mg (10 mL) taken once daily with or without food.
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 ].
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 ].
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 and Clinical Pharmacology ].
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 and Clinical Pharmacology ].
Oral Suspension: 20 mg/5 mL; white to off-white opaque suspension with a peppermint flavor.
Pregnancy
Risk Summary
Pregnant women with untreated pulmonary arterial hypertension are at risk for adverse maternal and fetal outcomes (see Clinical Considerations). Available data from a randomized controlled trial, observational studies, and case series with tadalafil use in pregnant women have not identified a 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 7 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 a 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 Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.
Data
Animal Data
Tadalafil 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 7 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, a 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 5 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 8 times the exposure at the MRHD. Surviving offspring had normal development and reproductive performance.
Lactation
Risk Summary
There 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 a 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 mother's clinical need for TADLIQ and any potential adverse effects on the breastfed child from TADLIQ or from the underlying maternal condition.
Females and Males of Reproductive Potential
Infertility
Males
Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. There was no adverse effect of tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone. The clinical significance of the decreased sperm concentrations in the two studies is unknown. There have been no studies evaluating the effect of tadalafil on fertility in men or women [see Clinical Pharmacology ].
Pediatric Use
Safety and effectiveness of TADLIQ in pediatric patients have not been established.
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 8 percent were 75 and over. No overall differences in safety were observed between subjects over 65 years of age compared to younger subjects or those over 75 years of age. No dose adjustment is warranted based on age alone; however, a greater sensitivity to medications in some older individuals should be considered. [See Clinical Pharmacology ].
Renal Impairment
For patients with mild or moderate renal impairment, start TADLIQ at 20 mg (5 mL) once daily. Increase the dose to 40 mg (10 mL) once daily based upon individual tolerability [see Dosage and Administration and Clinical Pharmacology ].
In patients with severe renal impairment, avoid use of TADLIQ because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Clinical Pharmacology ].
Hepatic Impairment
Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A or B), consider a starting dose of TADLIQ 20 mg (5 mL) once daily. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, thus avoid use of TADLIQ in such patients [see Dosage and Administration and Clinical Pharmacology ].
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 ].
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.
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 ].
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.
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.
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.
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 ].
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.
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.