Prescription Drug Information: Tadalafil (Page 4 of 9)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of tadalafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.

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. 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 [see Warnings and Precautions ( 5.1)].

Body as a Whole — hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis

Nervous — migraine, seizure and seizure recurrence, transient global amnesia

Ophthalmologic — visual field defect, retinal vein occlusion, retinal artery occlusion

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 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 [see Warnings and Precautions ( 5.4)].

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 ( 5.5)].

Urogenital — priapism [see Warnings and Precautions ( 5.3)].

To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

7.1 Potential for Pharmacodynamic Interactions with Tadalafil

Nitrates — Administration of tadalafil to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken tadalafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring [see Dosage and Administration ( 2.7), Contraindications ( 4.1), and Clinical Pharmacology ( 12.2)].

Alpha-Blockers — Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including tadalafil, 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, tamsulosin or alfuzosin. [see Dosage and Administration ( 2.7), Warnings and Precautions ( 5.6), and Clinical Pharmacology ( 12.2)].

Antihypertensives — PDE5 inhibitors, including tadalafil, 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, bendrofluazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo. [see Warnings and Precautions ( 5.6) and Clinical Pharmacology ( 12.2)].

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 tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. [see Warnings and Precautions ( 5.9) and Clinical Pharmacology ( 12.2)].

7.2 Potential for Other Drugs to Affect Tadalafil

[See Dosage and Administration ( 2.7) and Warnings and Precautions ( 5.10)].

Antacids — Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.

H 2 Antagonists (e.g. Nizatidine) — An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.

Cytochrome P450 Inhibitors — Tadalafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure.

CYP3A4 (e.g., Ketoconazole) — Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased tadalafil 20 mg single-dose exposure (AUC) by 312% and C max by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10 mg single-dose exposure (AUC) by 107% and C max by 15%, relative to the values for tadalafil 10 mg alone [see Dosage and Administration ( 2.7)].

Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.

HIV Protease inhibitor — Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20 mg single-dose exposure (AUC) by 32% with a 30% reduction in C max , relative to the values for tadalafil 20 mg alone. Ritonavir (200 mg twice daily), increased tadalafil 20 mg single-dose exposure (AUC) by 124% with no change in C max , relative to the values for tadalafil 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure [see Dosage and Administration ( 2.7)].

Cytochrome P450 Inducers — Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure.

CYP3A4 (e.g., Rifampin) — Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10 mg single-dose exposure (AUC) by 88% and C max by 46%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. No dose adjustment is warranted. The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of tadalafil for once daily use; the magnitude of decreased efficacy is unknown.

7.3 Potential for Tadalafil to Affect Other Drugs

Aspirin — Tadalafil did not potentiate the increase in bleeding time caused by aspirin.

Cytochrome P450 Substrates — Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.

CYP1A2 (e.g. Theophylline) — Tadalafil had no significant effect on the pharmacokinetics of theophylline. When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed.

CYP2C9 (e.g. Warfarin) — Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin.

CYP3A4 (e.g. Midazolam or Lovastatin) — Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin.

P-glycoprotein (e.g. Digoxin)— Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Tadalafil tablets are not indicated for use in females. There are no data with the use of tadalafil in pregnant women to inform any drug-associated risks for adverse developmental 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 up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day (see Data).

Data

Animal Data

Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given orally to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis. In a prenatal/postnatal developmental study in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 10 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 16 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance.

In another rat prenatal and postnatal development study at doses of 60, 200, and 1,000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg.

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

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