Vybrique Drug Information

1. INDICATION S AND USAGE VYBRIQUE TM is indicated for the treatment of erectile dysfunction. VYBRIQUE is a phosphodiesterase-5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (ED).

Recommended Dosage For most patients, the recommended dosage is 50 mg orally

administered on the tongue, taken as needed, approximately 1 hour before sexual activity. However, VYBRIQUE may be taken anywhere from 30 minutes to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day.

Based on effectiveness and tolerability the dosage may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg, not to exceed once per day. For administration instructions, see Dosage and Administration .

Dosage Modifications for Drug Interactions Nitrates

Concomitant use of nitrates in any form is contraindicated . Alpha Blockers Initiate VYBRIQUE at 25 mg orally in patients on concomitant therapy with an alpha-blocker. Patients should be stable on alpha-blocker therapy prior to initiating VYBRIQUE . For administration instructions, see Dosage and Administration . Ritonavir The maximum recommended dose and dosing frequency is 25 mg orally taken once within a 48-hour period in ritonavir-treated patients. Concomitant administration of ritonavir increased the blood levels of sildenafil by 11-fold . For administration instructions, see Dosage and Administration . Other CYP3A4 Inhibitors The recommended starting dosage is 25 mg orally, in patients taking strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin.

Clinical data have shown that co-administration with saquinavir or erythromycin increased blood levels of sildenafil by about 3-fold . For administration instructions, see Dosage and Administration .

Recommended Dosage in Specific Populations Age G reater than 6 5 years

The recommended starting dosage is 25 mg orally in patients greater than 65 years of age. For administration instructions, see Dosage and Administration . Renal Impairment The recommended starting dosage is 25 mg orally, in patients with severe renal impairment (creatinine clearance less than 30 mL/minute). The recommended starting dosage is 50 mg, in patients with mild (creatinine clearance 50 to 80 mL/min) and moderate (creatinine clearance 30 to 49 mL/min) renal impairment. For administration instructions, see Dosage and Administration . Hepatic Impairment The recommended starting dosage is 25 mg orally in patients with any degree of hepatic impairment.

In volunteers with mild and moderate degrees of hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for Cmax and 85% for AUC), and the pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. For administration instructions, see Dosage and Administration .

Important

Administration Instructions Administer VYBRIQUE orally with or without food. Place the oral film directly onto the tongue, where it will disintegrate and can then be swallowed with saliva without the need for water or other liquids. Do not cut or chew VYBRIQUE.

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 clinical practice. Sildenafil was administered to over 3700 patients (aged 19-87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year.

In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for sildenafil (2.5%) was not significantly different from placebo (2.3%). In fixed-dose studies, the incidence of some adverse reactions increased with dose. The type of adverse events in flexible-dose studies was similar to that for fixed dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 but generally were reported more frequently.

Table 1: Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil and More Frequent than Placebo in Fixed-Dose Clinical Studies Adverse Reaction 25 mg (n=312) 50 mg (n=511) 100 mg (n=506) Placebo (n=607) Headache 16% 21% % 28 % 7 Flushing 10% 19% 18% 2% Dyspepsia 3% 9% 17% 2% Abnormal vision† 1% 2% 11% 1% Nasal congestion 4% 4% 9% 2% Back pain 3% 4% 4% 2% Myalgia 2% 2% 4% 1% Nausea 2% 3% 3% 1% Dizziness 3% 4% 3% 2% Rash 1% 2% 3% 1% †Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. When sildenafil was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took sildenafil at least once weekly, and the following adverse reactions were reported: Table 2 : Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil and More Frequent than Placebo in Flexible-Dose Clinical Studies Adverse Reaction Sildenafil N=734 Placebo N=725 Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Abnormal Vision† 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% †Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision.

When VYBRIQUE was taken as recommended (on an as-needed basis) in a flexible-dose, placebo-controlled clinical trial of twelve weeks duration, patients took VYBRIQUE at least once weekly, not more than once per day, and the following adverse reactions were reported: Table 3: Adverse Reactions Reported by ≥2% of Patients Treated with VYBRIQUE and More Frequent than Placebo in a Flexible-Dose Clinical Study Adverse Reactions VYBRIQUE N=354 PLACEBO N=121 Headache 11% 4% Flushing 4% 0% Dyspepsia 4% 1% Nasal Congestion 3% 0% Dizziness 2% 0% In this study, none of the patients discontinued due to adverse reactions to VYBRIQUE. The following events occurred in <2% of patients in controlled clinical trials of sildenafil; a causal relationship to sildenafil is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful: Body as a Whole: face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury. Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy.

Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis. Hemic and Lymphatic: anemia and leukopenia. Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.

Musculoskeletal: arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis. Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia. Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased.

Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis. Special Senses: sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye hemorrhage, cataract, dry eyes. Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia.

Analysis of the safety database from sildenafil controlled clinical trials showed no apparent difference in adverse reactions in patients taking sildenafil with and without antihypertensive medication. This analysis was performed retrospectively and was not powered to detect any pre-specified difference in adverse reactions.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of sildenafil. 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 C erebrovascular : serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of sildenafil. 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 sildenafil without sexual activity.

Others were reported to have occurred hours to days after the use of sildenafil and sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors. Hemic and Lymphatic : vaso-occlusive crisis: In a small, prematurely terminated study of sildenafil in patients with pulmonary arterial hypertension (PAH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported in patients who received sildenafil than in those randomized to placebo.

The clinical relevance of this finding to men treated with sildenafil for ED is not known. Nervous: seizure, seizure recurrence, anxiety, and transient global amnesia. Respiratory: epistaxis Special senses: Hearing: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including sildenafil.

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 sildenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors.

Ocular: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal edema, retinal vascular disease or bleeding, and vitreous traction/detachment. Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing 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 . Urogenital : prolonged erection, priapism, and hematuria.

Nitrates

Administration of sildenafil with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates .

Alpha-blockers Use caution when co-administering alpha-blockers with sildenafil because of potential additive

blood pressure lowering effects. When sildenafil is co-administered with an alpha-blocker, patients should be stable on alpha blocker therapy prior to initiating sildenafil treatment and sildenafil should be initiated at the lowest dose .

Amlodipine

When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

Ritonavir and other

CYP3A4 inhibitors Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose of 25 mg of sildenafil in a 48 hour period. Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in 160% and 182% increases in sildenafil Cmax and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil Cmax and AUC, respectively.

Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of sildenafil should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole).

Alcohol

In a drug-drug interaction study of sildenafil 50 mg given with alcohol 0.5 g/kg, in which mean maximum blood alcohol levels of 0.08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers .

Pregnancy Risk Summary VYBRIQUE is not indicated for use in females. There are no data with the use of VYBRIQUE in pregnant women to inform any drug-associated risks for adverse developmental outcomes. Animal reproduction studies conducted with sildenafil did not show adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to 16 and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m2 basis ( see Data ). Data Animal Data No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received oral doses up to 200 mg/kg/day during organogenesis.

These doses represent, respectively, about 16 and 32 times the MRHD on a mg/m2 basis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m2 basis in a 50 kg subject.

Pediatric Use VYBRIQUE is not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients.

Nitrates Consistent with its known effects on the nitric oxide/cGMP pathway

VYBRIQUE potentiates the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated. After patients have taken VYBRIQUE it is unknown when nitrates, if necessary, can be safely administered. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point.

Hypersensitivity Reactions

VYBRIQUE is contraindicated in patients with a known hypersensitivity to sildenafil or any VYBRIQUE component. Hypersensitivity reactions, including rash and urticaria, have been reported .

Concomitant Guanylate Cyclase (GC) Stimulators Do not use

VYBRIQUE in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including VYBRIQUE, may potentiate the hypotensive effects of GC stimulators.

In studies in healthy volunteers administered single sildenafil doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but incidence rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.