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). ( 1 )
Contraindications
4. CONTRAINDICATIONS Administration of VYBRIQUE to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form. VYBRIQUE was shown to potentiate the hypotensive effect of nitrates. ( 4.1 , 7.1 , 12.2 ) Known hypersensitivity to sildenafil or any component of oral film. ( 4.2 ) Administration with guanylate cyclase (GC) stimulators, such as riociguat. ( 4.3 )
4.1Nitrates Consistent
with its known effects on the nitric oxide/cGMP pathway [ see Clinical Pharmacology ( 12.1 , 12.2 ) ] , 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 [ see Dosage and Administration ( 2.2 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 ) ].
4.2Hypersensitivity 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 [ see Adverse Reactions ( 6.1 ) ] .
4.3Concomitant 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.
Warnings and precautions
5. WARNINGS AND PRECAUTIONS Patients should not use VYBRIQUE if sexual activity is inadvisable due to cardiovascular status. ( 5.1 ) Patients should seek emergency treatment if an erection lasts >4 hours. Use VYBRIQUE with caution in patients predisposed to priapism. ( 5.2 ) Patients should stop VYBRIQUE and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of non-arteritic anterior ischemic optic neuropathy (NAION).
VYBRIQUE should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a “crowded” optic disc may also be at an increased risk of NAION. ( 5.3 ) Patients should stop VYBRIQUE and seek prompt medical attention in the event of sudden decrease or loss of hearing. ( 5.4 ) Caution is advised when VYBRIQUE is co-administered with alpha-blockers or antihypertensives.
Concomitant use may lead to hypotension. ( 5.5 ) Decreased blood pressure, syncope, and prolonged erection may occur at higher sildenafil exposures. In patients taking strong CYP inhibitors such as ritonavir, sildenafil exposure is increased. Decrease in VYBRIQUE dosage is recommended. ( 2.2 , 5.6 )
5.1Cardiovascular Risk General
There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including VYBIRQUE should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. The following groups of patients were not included in clinical safety and efficacy trials for sildenafil, and therefore, until further information is available, VYBRIQUE is not recommended for use in the following groups: Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months Patients with resting hypotension (BP <90/50 mmHg) or hypertension (BP >170/110 mmHg) Patients with cardiac failure or coronary artery disease causing unstable angina.
Blood Pressure Decreases Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be sensitive to the actions of vasodilators, including VYBRIQUE. As with other PDE5 inhibitors, VYBRIQUE has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers.
In healthy subjects aged 18 to 45 years, VYBRIQUE 100 mg resulted in mean maximal decreases relative to placebo of 6 mmHg systolic and 3 mmHg diastolic. In healthy subjects aged 65 years and older, VYBRIQUE 100 mg resulted in mean maximal decreases relative to placebo of 14 mmHg systolic and 8 mmHg diastolic [ see Clinical Pharmacology ( 12.2 ) ]. Prior to prescribing VYBRIQUE, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.
5.2Prolonged Erection and Priapism
Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of sildenafil. In the event of an erection that persists longer than 4 hours, instruct the patient to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. Use VYBRIQUE with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
5.3Effects on the Eye
Advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including VYBRIQUE and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors.
Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged 50 years and older. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34).
A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare post-marketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [see Adverse Reactions ( 6.2 ) ] .
Consider whether patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, use PDE5 inhibitors, including VYBRIQUE with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including VYBRIQUE, for this uncommon condition.
Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the sildenafil citrate clinical trials, and use in these patients is not recommended.
5.4Sudden Hearing Loss
Advise patients to stop taking PDE5 inhibitors, including VYBRIQUE and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including sildenafil. 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 ( 6.1 , 6.2 ) ].
5.5 Hypotension when Co-administered with Alpha-blockers or Antihypertensives Alpha-blockers Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including sildenafil, 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 occur. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [ see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.2 ) ] leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).
Consider the following: Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. In patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose [see Dosage and Administration ( 2.2 ) ] .
In patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor. Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti
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Interactions
7. DRUG INTERACTIONS VYBRIQUE can potentiate the hypotensive effects of nitrates, alpha blockers, and antihypertensives. ( 4.1 , 5.5 , 7.1 , 7.2 , 7.3 , 12.2 ) With concomitant use of alpha blockers, initiate VYBRIQUE at 25 mg dose. ( 2.2 ) CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin) increase VYBRIQUE exposure. ( 2.2 , 7.4 , 12.3 ) Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48- hour period.
( 2.2 , 5.6 ) Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg. ( 2.2 , 7.4 )
7.1Nitrates 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 [see Dosage and Administration ( 2.2 ), Contraindications ( 4.1 ), Clinical Pharmacology ( 12.2 ) ] .
7.2Alpha-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 [see Dosage and Administration ( 2.2 ),Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.2 ) ] .
7.3Amlodipine
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 [ see Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.2 )].
7.4Ritonavir
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 [ see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.6 ), Clinical Pharmacology ( 12.3 ) ]. 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) [ see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 ) ].
7.5 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 [see Clinical Pharmacology ( 12.2 ) ] .
Pregnancy and breastfeeding
8.1Pregnancy 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.
Adverse reactions
6. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Cardiovascular [see Warnings and Precautions ( 5.1 )] Prolonged Erection and Priapism [see Warnings and Precautions ( 5.2 )] Effects on the Eye [see Warnings and Precautions ( 5.3 )] Hearing Loss [see Warnings and Precautions ( 5.4 )] Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [see Warnings and Precautions ( 5.5 ) ] Adverse Reactions with the Concomitant Use of Ritonavir [see Warnings and Precautions 5.6 )] Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [see Warnings and Precautions ( 5.7 ) ] Effects on Bleeding [see Warnings and Precautions ( 5.8 ) ] The most common adverse reactions reported in clinical trials (≥ 2%) of sildenafil are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.
Most common adverse reactions (≥ 2%) include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact IBSA Pharma Inc. at 1-800-587-3513 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical 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.
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.
6.2Postmarketing 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 [see Warnings and Precautions ( 5.1 ) and Patient Counseling Informati
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Composition
Active ingredients
SILDENAFIL CITRATE EQ 100MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
