Fiable

Fiable is an oral therapy for the treatment of erectile dysfunction. It is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMPspecific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.

Fiable hydrochloride orally disintegrating tablets are indicated for the treatment of erectile dysfunction.

Fiable is used to treat men who have erectile dysfunction (also called sexual impotence). Fiable belongs to a group of medicines called phosphodiesterase 5 (PDE5) inhibitors. These medicines prevent an enzyme called phosphodiesterase type-5 from working too quickly. The penis is one of the areas where this enzyme works.

Erectile dysfunction is a condition where the penis does not harden and expand when a man is sexually excited, or when he cannot keep an erection. When a man is sexually stimulated, his body's normal response is to increase blood flow to his penis to produce an erection. By controlling the enzyme, Fiable helps to maintain an erection after the penis is stroked by increasing blood flow to the penis. Without physical action to the penis, such as that occurring during sexual intercourse, Fiable will not work to cause an erection.

Fiable is available only with your doctor's prescription.

General

Fiable is available in 10 mg orally disintegrating tablets. Fiable is not interchangeable with Fiable 10 mg film-coated tablets (Fiable). Fiable provides higher systemic exposure compared to Fiable 10 mg film-coated tablets (Fiable).

Fiable should be taken orally, as needed, approximately 60 minutes before sexual activity. The maximum dosing frequency is one Fiable tablet per day. Sexual stimulation is required for a response to treatment.

Fiable should be placed on the tongue where it will disintegrate. The tablet should be taken without liquid. It should be taken immediately upon removal from the blister.

Those patients who require a lower or higher dose of Fiable need to be prescribed Fiable film-coated tablets.

Use With Food

Fiable can be taken with or without food.

Use In Special Populations

Hepatic Impairment

Do not use Fiable in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

Renal Impairment

Do not use Fiable in patients on renal dialysis.

Concomitant Medications

Nitrates

Concomitant use with nitrates in any form is contraindicated.

Guanylate Cyclase (GC) Stimulators, such as riociguat

Concomitant use is contraindicated.

CYP3A4 Inhibitors

Do not use Fiable with potent or moderate CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, clarithromycin and erythromycin.

Alpha-Blockers

In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a phosphodiesterase (PDE5) inhibitor including Fiable. In patients taking alpha-blockers, do not initiate Fiable therapy with Fiable. Lower doses of Fiable film-coated tablets should be used as initial therapy in these patients. Patients taking alpha-blockers who have previously used Fiable film-coated tablets may change to Fiable at the advice of their healthcare provider.

A time interval between dosing should be considered when Fiable is prescribed concomitantly with alpha-blocker therapy.

How supplied

Dosage Forms And Strengths

Fiable is available in 10 mg white, round, orally disintegrating tablets (not scored), no debossing.

Storage And Handling

Fiable (Fiable HCl) are white, round orally disintegrating tablets with no debossing. Fiable orally disintegrating tablets are packaged into foil blisterpacks and supplied as a 4 tablet unit.

In addition to the active ingredient, Fiable, each tablet contains aspartame, peppermint flavor, magnesium stearate, and Pharmaburst™ B2 (crospovidone, mannitol, silica colloidal hydrated, and sorbitol).

Recommended Storage

Store Fiable at 25°C (77°F); excursions permitted to 15–30°C (59–86°F).

Fiable is dispensed in blisterpacks. The patient should be advised to examine the blisterpack before use and not use if blisters are torn, broken, or missing.

Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 Manufactured in Germany. Distributed by: GlaxoSmithKline Research Triangle Park NC 27709. Revision Date 09/2015

See also:
What is the most important information I should know about Fiable?

Nitrates

Administration of Fiable hydrochloride orally disintegrating tablets with nitrates (either regularly and/or intermittently) and nitric oxide donors is contraindicated. Consistent with the effects of PDE5 inhibition on the nitric oxide/cyclic guanosine monophosphate pathway, PDE5 inhibitors, including Fiable hydrochloride orally disintegrating tablets, may potentiate the hypotensive effects of nitrates. A suitable time interval following Fiable hydrochloride orally disintegrating tablets dosing for the safe administration of nitrates or nitric oxide donors has not been determined.

Guanylate Cyclase (GC) Stimulators

Do not use Fiable hydrochloride orally disintegrating tablets in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including Fiable hydrochloride orally disintegrating tablets may potentiate the hypotensive effects of GC stimulators.

Use Fiable orally disintegrating tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Fiable orally disintegrating tablets. Talk to your pharmacist if you have questions about this information.
• Take Fiable orally disintegrating tablets by mouth with or without food.
• Take Fiable orally disintegrating tablets about 1 hour before sexual activity.
• Do not take Fiable orally disintegrating tablets more often than once daily or as directed by your doctor.
• Be sure your hands are completely dry before you remove Fiable orally disintegrating tablets from the blister.
• Take Fiable orally disintegrating tablets immediately after you remove it from the blister. Do not store the removed tablet for future use.
• Do not crush or split Fiable orally disintegrating tablets. Place Fiable orally disintegrating tablets on the tongue. Allow it to completely dissolve.
• Take Fiable orally disintegrating tablets without liquid.
• Do not eat grapefruit or drink grapefruit juice while you use Fiable orally disintegrating tablets.
• If you miss a dose of Fiable orally disintegrating tablets and you still intend to engage in sexual activity, take it as soon as you remember. Continue to take it as directed by your doctor.

Ask your health care provider any questions you may have about how to use Fiable orally disintegrating tablets.

Use: Labeled Indications

Erectile dysfunction: Treatment of erectile dysfunction (ED)

Off Label Uses

Pulmonary arterial hypertension

Data from a small, randomized, double-blinded, placebo-controlled trial suggest that Fiable may be beneficial for the treatment of pulmonary arterial hypertension (WHO Group I; efficacy established in patients with WHO/NYHA functional class II and III) in adults by improving exercise ability and hemodynamics and delaying clinical worsening. Access Full-Off Label Monograph.

See also:
What other drugs will affect Fiable?

The drug interaction studies described below were conducted using Fiable film-coated tablets.

Potential For Pharmacodynamic Interactions With Fiable

Nitrates

Concomitant use of Fiable and nitrates is contraindicated. The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after Fiable and increases in heart rate when taken at 1, 4 and 8 hours after Fiable were potentiated by a 20 mg dose of Fiable in healthy middle-aged subjects. These effects were not observed when Fiable 20 mg was taken 24 hours before the nitroglycerin (NTG). Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of Fiable and nitrates is contraindicated.

Alpha-Blockers

Patients taking alpha-blockers should not initiate Fiable therapy with Fiable. Patients treated with alpha-blockers who have previously used Fiable film-coated tablets may be switched to Fiable at the advice of their healthcare provider. Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including Fiable 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 co-administration of Fiable with alfuzosin, terazosin or tamsulosin.

Antihypertensives

Fiable may add to the blood pressure lowering effect of antihypertensive agents. In a clinical pharmacology study of patients with erectile dysfunction, single doses of 20 mg Fiable caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute. The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing. Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1.

Alcohol

Fiable 20 mg did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person). Alcohol and Fiable plasma levels were not altered when dosed simultaneously.

Effect Of Other Drugs On Fiable

In vitro studies

Studies in human liver microsomes showed that Fiable is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce Fiable clearance.

In Vivo Studies

Do not use Fiable with moderate and potent CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of Fiable is increased in their presence.

Potent CYP3A4 Inhibitors

Ketoconazole (200 mg once daily) produced a 10-fold increase in Fiable area under the curve (AUC) and a 4-fold increase in maximum concentration (Cmax) when co-administered with Fiable 5 mg in healthy volunteers.

Indinavir (800 mg t.i.d.) co-administered with Fiable 10 mg resulted in a 16-fold increase in Fiable AUC, a 7-fold increase in Fiable Cmax and a 2-fold increase in Fiable half-life.

Ritonavir (600 mg b.i.d.) co-administered with Fiable 5 mg resulted in a 49-fold increase in Fiable AUC and a 13fold increase in Fiable Cmax. The interaction is a consequence of blocking hepatic metabolism of Fiable by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9.

Moderate CYP3A4 Inhibitors

Erythromycin (500 mg t.i.d.) produced a 4-fold increase in Fiable AUC and a 3-fold increase in Fiable Cmax when co-administered with Fiable 5 mg in healthy volunteers.

Other Drug Interactions

No pharmacokinetic interactions were observed between Fiable and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, Fiable had no effect on the prothrombin time or other pharmacodynamic parameters.

Cimetidine (400 mg b.i.d.) had no effect on AUC and Cmax of Fiable when co-administered with 20 mg Fiable in healthy volunteers.

Effects Of Fiable On Other Drugs

In Vitro Studies

Fiable and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki > 100 micromolar). Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing. The most potent inhibitory activity was observed for Fiable metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 Cmax values after an 80 mg Fiable dose.

In Vivo Studies

Nifedipine: Fiable 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of Fiable when taken in combination. In these patients whose hypertension was controlled with nifedipine, Fiable 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.

Ritonavir and Indinavir: Upon concomitant administration of 5 mg Fiable with 600 mg b.i.d. ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of Fiable (film-coated tablets) with 800 mg t.i.d. indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.

Aspirin: Fiable 10 mg and 20 mg did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).

Other Interactions: Fiable had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

See also:
What are the possible side effects of Fiable?

The following serious adverse reactions with the use of Fiable (Fiable) are discussed elsewhere in the labeling:

• Cardiovascular effects
• Priapism
• QT Prolongation
• Effects on eye
• Sudden hearing loss

Clinical Studies 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 practice.

Fiable: Safety of Fiable was evaluated in two identical multi-national, randomized, double-blind, placebo-controlled trials. In both pivotal studies, enrollment was stratified so that approximately 50% of patients were ≥ 65 years old. Approximately 8% (n=29) were ≥ 75 years old. An integrated analysis of both studies included a total of 355 subjects that received Fiable compared to 340 subjects that received placebo (mean age was 61.7, range 21.0 to 88.0; 68% White, 5% Black, 6% Asian, 11% Hispanic and 11% Other). The discontinuation rates due to adverse reactions were 1.4% for Fiable compared to 0.6% for placebo. Table 1 below details the most frequently reported adverse reactions.

Table 1: Adverse drug reactions reported by ≥ 2% of the patients treated with Fiable and more frequent on drug than placebo in controlled trials

Adverse drug reactions reported in the Fiable placebo controlled trials were comparable to the adverse drug reactions reported in earlier Fiable film-coated tablets placebo controlled trials.

All Fiable Studies

Fiable film-coated tablets and Fiable has been administered to over 17,000 men (mean age 54.5, range 18–89 years; 70% White, 5% Black, 13% Asian, 4% Hispanic and 8% Other) during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year.

In the placebo-controlled clinical trials for Fiable film-coated tablets and Fiable, the discontinuation rate due to adverse events was 1.9% for Fiable compared to 0.8% for placebo.

Placebo-controlled trials suggested a dose effect in the incidence of some adverse reactions (for example, dizziness, headache, flushing, dyspepsia, nausea, nasal congestion) over the 5 mg, 10 mg, and 20 mg doses of Fiable film-coated tablets.

The following section identifies additional, less frequent adverse reactions ( < 2%) reported during the clinical development of Fiable film-coated tablets and Fiable. Excluded from this list are those adverse reactions that are infrequent and minor, those events that may be commonly observed in the absence of drug therapy, and those events that are not reasonably associated with the drug:

Body as a whole: allergic edema and angioedema, feeling unwell, allergic reactions, chest pain

Auditory: tinnitus, vertigo

Cardiovascular: palpitation, tachycardia, angina pectoris, myocardial infarction, ventricular tachyarrhythmias, hypotension

Digestive: nausea, gastrointestinal and abdominal pain, dry mouth, diarrhea, gastroesophageal reflux disease, gastritis, vomiting, increase in transaminases

Musculoskeletal: increase in creatine phosphokinase (CPK), increased muscle tone and cramping, myalgia

Nervous: paresthesia and dysesthesia, somnolence, sleep disorder, syncope, amnesia, seizure

Respiratory: dyspnea, sinus congestion

Skin and appendages: erythema, rash

Ophthalmologic: visual disturbance, ocular hyperemia, visual color distortions, eye pain and eye discomfort, photophobia, increase in intraocular pressure, conjunctivitis

Urogenital: increase in erection, priapism

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Fiable in the film-coated tablet formulation. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Ophthalmologic

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 Fiable. 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. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Visual disturbances including vision loss (temporary or permanent), such as visual field defect, retinal vein occlusion, and reduced visual acuity, have also been reported rarely in postmarketing experience. It is not possible to determine whether these events are related directly to the use of Fiable.

Neurologic

Seizure, seizure recurrence and transient global amnesia have been reported postmarketing in temporal association with Fiable.

Otologic

Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including Fiable. In some 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 Fiable, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors.