Cialis Warnings, Precautions, Pregnancy, Nursing, Abuse - Tadalafil

Cialis Warnings, Precautions, Pregnancy, Nursing, Abuse - Tadalafil

WARNINGS

General — Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including CIALIS, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status.

Left Ventricular Outflow Obstruction — Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors.

The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for CIALIS, and, therefore, the use of CIALIS is not recommended in these groups until further information is available: - patients with a myocardial infarction within the last 90 days

- patients with unstable angina or angina occurring during sexual intercourse

- patients with New York Heart Association Class 2 or greater heart failure in the last 6 months

- patients with uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension (>170/100 mm Hg)

- patients with a stroke within the last 6 months

In addition, 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.

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. 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.

Evaluation of erectile dysfunction should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options. Before prescribing CIALIS, it is important to note the following:

CIALIS should be limited to 5 mg not more than once daily in patients with severe renal insufficiency or end-stage renal disease. The starting dose of CIALIS in patients with a moderate degree of renal insufficiency should be 5 mg not more than once daily, and the maximum dose should be limited to 10 mg not more than once in every 48 hours. No dose adjustment is required in patients with mild renal insufficiency (see Pharmacokinetics in Special Populations under CLINICAL PHARMACOLOGY).

In patients with mild or moderate hepatic impairment, the dose of CIALIS should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of CIALIS in this group is not recommended (see Pharmacokinetics in Special Populations under CLINICAL PHARMACOLOGY).

CIALIS is metabolized predominantly by CYP3A4 in the liver. The dose of CIALIS should be limited to 10 mg no more than once every 72 hours in patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole (see Effects of Other Drugs on CIALIS under Drug Interactions).

As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects (see Clinical Studies under CLINICAL PHARMACOLOGY). While this effect should not be of consequence in most patients, prior to prescribing CIALIS, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with significant left ventricular outflow obstruction or severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators.

The safety and efficacy of combinations of CIALIS and other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended. CIALIS should be used with caution in patients who have 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). When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. CIALIS has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although CIALIS has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment and caution.

INFORMATION FOR PATIENTS

Physicians should discuss with patients the contraindication of CIALIS with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of CIALIS with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke. Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of CIALIS. In such a patient, who has taken CIALIS, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking CIALIS should seek immediate medical attention. Physicians should inform their patients that concomitant use of CIALIS with alpha-adrenergic antagonists (other than 0.4 mg once-daily tamsulosin) is contraindicated because coadministration can lead to significant reductions in blood pressure. Physicians should discuss with patients the potential for CIALIS to augment the blood-pressure-lowering effect of other anti-hypertensive medications. Patients should be made aware that both alcohol and CIALIS, 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. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with CIALIS can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Physicians should consider the potential cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention. There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. 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. The use of CIALIS offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered. Patients should read the patient leaflet entitled "INFORMATION FOR THE PATIENT" before starting therapy with CIALIS and each time the prescription is renewed or refilled.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 10-fold for mice, and 14- and 26-fold for male and female rats, respectively, the exposures in human males given Maximum Recommended Human Dose (MRHD) of 20 mg.

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.

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, a dose producing AUCs for unbound tadalafil of 14-fold for males or 26-fold for females the exposures observed in human males given the MRHD of 20 mg. In beagle dogs given tadalafil daily for 3 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 a decrease in spermatogenesis in 40-75% of the dogs at doses of ³10 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 20 mg.

There were no treatment-related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.

In men, there were no clinically relevant effects on sperm concentration, sperm count, motility, or morphology in placebo-controlled studies of daily doses of tadalafil 10 mg (N=204) or 20 mg (N=217) for 6 months. In addition, tadalafil had no effect on serum levels of testosterone, luteinizing hormone, or follicle stimulating hormone in males.

Animal Toxicology

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 2- to 33-fold above the human exposure (AUCs) at the MRHD of 20 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1- and 6-month studies at unbound tadalafil exposure of 1- to 54-fold above the human exposure (AUC) at the MRHD of 20 mg. In a 12-month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 14- to 18-fold the human exposure at the MRHD of 20 mg. The abnormal blood-cell findings were reversible within 2 weeks upon removal of the drug.

Pregnancy, Nursing Mothers, and Pediatric Use

CIALIS is not indicated for use in newborns, children, or women.

Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats. Tadalafil and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma. Following a single-oral dose of 10 mg/kg, approximately 0.1% of the total radioactive dose was excreted into the milk within 3 hours. It is not known if tadalafil and/or its metabolites is excreted in human breast milk. Use of tadalafil in nursing mothers is not recommended.

Pregnancy Category B — There was no evidence of teratogenicity, embryotoxicity, or fetotoxicity in rat or mouse fetuses that received up to 1000 mg/kg/day during the major organ development. Plasma exposure at this dose is approximately 11-fold greater than the AUC values for unbound tadalafil in humans given the MRHD of 20 mg. In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, there was a reduction in postnatal survival of pups. The no-observed-effect-level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day, which gives approximately 16- and 10-fold exposure multiples, respectively, of the human AUC for the MRHD dose of 20 mg. There are no adequate and well-controlled studies of tadalafil in pregnant women.

Geriatric Use

Approximately 25% of patients in the primary efficacy and safety studies of tadalafil were greater than 65 years of age. No overall differences in efficacy and safety were observed between older and younger patients. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered (see Special Populations under CLINICAL PHARMACOLOGY).