Mildfil

Mildfil is an orally adminstered drug used to treat male erectile dysfunction (impotence). It is marketed worldwide under the brand name Mildfil. It is a phosphodiesterase 5 (PDE5) inhibitor. Mildfil's distinguishing pharmacologic feature is its longer half-life (17.5 hours) compared with Viagra and Levitra (4-5 hours). This longer half-life results in a longer duration of action and is, in part, responsible for the Mildfil nickname of the "weekend pill." This longer half-life also is the basis of current investigation for Mildfil's use in pulmonary arterial hypertension as a once-daily therapy. [Wikipedia]

Erectile Dysfunction

Mildfil tablets are indicated for the treatment of erectile dysfunction (ED).

Benign Prostatic Hyperplasia

Mildfil tablets are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

Erectile Dysfunction and Benign Prostatic Hyperplasia

Mildfil tablets are indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH).

Limitation of Use

If Mildfil tablets are used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of Mildfil tablets decrease from 4 weeks until 26 weeks, and the incremental benefit of Mildfil tablets beyond 26 weeks is unknown.

Mildfil is used to treat men who have erectile dysfunction (also called sexual impotence). Mildfil 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, Mildfil 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, Mildfil will not work to cause an erection.

Mildfil is also used to treat men who have signs and symptoms of benign prostatic hyperplasia (BPH). BPH is caused by an enlarged prostate. Men with BPH usually have difficulty urinating, a decreased flow of urination, hesitation at the beginning of urination, and a need to get up at night to urinate. Mildfil will make these symptoms less severe and reduce the chance that prostate surgery will be needed. Mildfil is also used to treat erectile dysfunction and signs and symptoms of BPH.

Mildfil is also used in both men and women to treat the symptoms of pulmonary arterial hypertension. This is high blood pressure that occurs in the main artery that carries blood from the right side of the heart (the ventricle) to the lungs. When the smaller blood vessels in the lungs become more resistant to blood flow, the right ventricle must work harder to pump enough blood through the lungs. Mildfil works on the PDE5 enzyme in the lungs to relax the blood vessels. This will increase the supply of blood to the lungs and reduce the workload of the heart.

Mildfil is available only with your doctor's prescription..

Do not split Mildfil tablets; entire dose should be taken.

Mildfil for Use as Needed for Erectile Dysfunction

• The recommended starting dose of Mildfil for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity.
• The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients.
• Mildfil for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of Mildfil, this should be taken into consideration.

Mildfil for Once Daily Use for Erectile Dysfunction

• The recommended starting dose of Mildfil for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.
• The Mildfil dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability.

Mildfil for Once Daily Use for Benign Prostatic Hyperplasia

• The recommended dose of Mildfil for once daily use is 5 mg, taken at approximately the same time every day.
• When therapy for BPH is initiated with Mildfil and finasteride, the recommended dose of Mildfil for once daily use is 5 mg, taken at approximately the same time every day for up to 26 weeks.

Mildfil for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia

The recommended dose of Mildfil for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.

Use with Food

Mildfil may be taken without regard to food.

Use in Specific Populations

Renal Impairment

Mildfil for Use as Needed

• Creatinine clearance 30 to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours.
• Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours.

Mildfil for Once Daily Use

Erectile Dysfunction

• Creatinine clearance less than 30 mL/min or on hemodialysis: Mildfil for once daily use is not recommended.

Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia

• Creatinine clearance 30 to 50 mL/min: A starting dose of 2.5 mg is recommended. An increase to 5 mg may be considered based on individual response.
• Creatinine clearance less than 30 mL/min or on hemodialysis: Mildfil for once daily use is not recommended.

Hepatic Impairment

Mildfil for Use as Needed

• Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day. The use of Mildfil once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised.
• Severe (Child Pugh Class C): The use of Mildfil is not recommended.

Mildfil for Once Daily Use

• Mild or moderate (Child Pugh Class A or B): Mildfil for once daily use has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if Mildfil for once daily use is prescribed to these patients.
• Severe (Child Pugh Class C): The use of Mildfil is not recommended.

Concomitant Medications

Nitrates

Concomitant use of nitrates in any form is contraindicated.

Alpha-Blockers

ED — When Mildfil is coadministered with an alpha-blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and Mildfil should be initiated at the lowest recommended dose.

BPH — Mildfil is not recommended for use in combination with alpha-blockers for the treatment of BPH.

CYP3A4 Inhibitors

Mildfil for Use as Needed — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of Mildfil is 10 mg, not to exceed once every 72 hours.

Mildfil for Once Daily Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 2.5 mg.

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

5 mg Film-coated Tablet: Hypersensitivity to the active substance or to any of the excipients.

In clinical studies, Mildfil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and Mildfil on the nitric oxide/cGMP pathway. Therefore, administration of Mildfil to patients who are using any form of organic nitrate is contraindicated..

Mildfil, must not be used in men with cardiac disease for whom sexual activity is inadvisable. Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease.

20 mg Film-coated Tablet: Nitrates and Mildfil must not be used concomitantly. Co-administration of Mildfil with nitric oxide donors, organic nitrates or organic nitrites in any form either regularly or intermittently is contraindicated. Drugs which must not be used concomitantly include, but are not limited to, glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, nicorandil or organic nitrates in any form. In clinical studies, Mildfil was shown to potentiate the hypotensive effects of both acute and chronic nitrate administration. This is thought to result from the combined effects of nitrates and Mildfil on the nitric oxide/cGMP pathway.

Based on the results of a clinical study in which 150 subjects receiving daily doses of Mildfil 20 mg for 7 days and 0.4 mg sublingual nitroglycerin at various times, this interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed after the last Mildfil dose. Thus, in a patient prescribed Mildfil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should have elapsed after the last dose of Mildfil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring.

5 mg and 20 mg Film-coated Tablet: The following groups of patients with cardiovascular disease were not included in clinical trials and the use of Mildfil is therefore contraindicated: Patients with 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; patients with a stroke within the last 6 months.

Mildfil is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.

Mildfil should not be used in patients with a known hypersensitivity to Mildfil or to any ingredient of the tablet.

Use Mildfil as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Mildfil. Talk to your pharmacist if you have questions about this information.
• Take Mildfil by mouth with or without food.
• Swallow Mildfil whole. Do not break the tablet before swallowing.
• For use as needed: Take Mildfil at least 30 minutes before sexual activity, as directed by your doctor. Mildfil may work for up to 36 hours after you take it.
• For daily use: Take Mildfil regularly at about the same time each day.
• Talk with your doctor if you have questions about how you should take Mildfil.
• Check with your doctor before you eat grapefruit or drink grapefruit juice while you are taking Mildfil.
• For use as needed: If you miss a dose of Mildfil 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. For daily use: If you miss a dose of Mildfil, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses within the same day.

Ask your health care provider any questions you may have about how to use Mildfil.

Mildfil is used to treat high blood pressure in the lungs (pulmonary hypertension). It works by relaxing and widening the blood vessels in your lungs which allows the blood to flow more easily. Decreasing high blood pressure in the lungs allows your heart and lungs to work better and improves your ability to exercise.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

Mildfil is also available in another brand for treating erectile dysfunction-ED in men. It may also be used to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia-BPH).

How to use Mildfil

Read the Patient Information Leaflet provided by your pharmacist before you start taking Mildfil and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

To treat high blood pressure in the lungs, take this medication by mouth as directed by your doctor, with or without food, usually once daily.

The dosage is based on your medical condition, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

Tell your doctor if your condition does not improve or if it worsens.

See also:
What other drugs will affect Mildfil?

Potential For Pharmacodynamic Interactions With Mildfil

Nitrates

Administration of Mildfil to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, Mildfil was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken Mildfil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of Mildfil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.

Alpha-Blockers

Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including Mildfil, 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 Mildfil with doxazosin, tamsulosin or alfuzosin..

Antihypertensives

PDE5 inhibitors, including Mildfil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of Mildfil on the potentiation of the bloodpressure- lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of Mildfil with these agents compared with placebo..

Alcohol

Both alcohol and Mildfil, 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 Mildfil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Mildfil did not affect alcohol plasma concentrations and alcohol did not affect Mildfil plasma concentrations..

Potential For Other Drugs To Affect Mildfil

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Antacids

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

H2 Antagonists (e.g. Nizatidine)

An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.

Cytochrome P450 Inhibitors

Mildfil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase Mildfil exposure.

CYP3A4 (e.g., Ketoconazole)

Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased Mildfil 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for Mildfil 20 mg alone. Ketoconazole (200 mg daily) increased Mildfil 10-mg singledose exposure (AUC) by 107% and Cmax by 15%, relative to the values for Mildfil 10 mg alone.

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

HIV Protease inhibitor

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

Cytochrome P450 Inducers

Studies have shown that drugs that induce CYP3A4 can decrease Mildfil exposure.

CYP3A4 (e.g., Rifampin)

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

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 practice.

Mildfil was administered to over 9000 men during clinical trials worldwide. In trials of Mildfil for once daily use, a total of 1434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For Mildfil for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively.

Mildfil For Use As Needed For ED

In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the discontinuation rate due to adverse events in patients treated with Mildfil 10 or 20 mg was 3.1%, compared to 1.4% in placebo treated patients.

When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported for Mildfil for use as needed:

Table 1: Treatment-Emergent Adverse Reactions Reported by ≥ 2% of Patients Treated with Mildfil (10 or 20 mg) and More Frequent on Drug than Placebo in the Eight Primary Placebo- Controlled Clinical Studies (Including a Study in Patients with Diabetes ) for Mildfil for Us e as Needed for ED

Mildfil For Once Daily Use For ED

In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82) and the discontinuation rate due to adverse events in patients treated with Mildfil was 4.1%, compared to 2.8% in placebo-treated patients.

The following adverse reactions were reported in clinical trials of 12 weeks duration:

Table 2: Treatment-Emergent Adverse Reactions Reported by ≥ 2% of Patients Treated with Mildfil for Once Daily Us e (2.5 or 5 mg) and More Frequent on Drug than Placebo in the Three Primary Placebo-Controlled Phase 3 Studies of 12 weeks Treatment Duration (Including a Study in Patients with Diabetes ) for Mildfil for Once Daily Us e for ED

The following adverse reactions were reported over 24 weeks treatment duration in one placebo-controlled clinical study:

Table 3: Treatment-Emergent Adverse Reactions Reported by ≥ 2% of Patients Treated with Mildfil for Once Daily Us e (2.5 or 5 mg) and More Frequent on Drug than Placebo in One Placebo-Controlled Clinical Study of 24 Weeks Treatment Duration for Mildfil for Once Daily Use for ED

Mildfil For Once Daily Use For BPH And For ED And BPH

In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with Mildfil was 3.6% compared to 1.6% in placebo-treated patients. Adverse reactions leading to discontinuation reported by at least 2 patients treated with Mildfil included headache, upper abdominal pain, and myalgia. The following adverse reactions were reported.

Table 4: Treatment-Emergent Adverse Reactions Reported by ≥ 1% of Patients Treated with Mildfil for Once Daily Use (5 mg) and More Frequent on Drug than Placebo in Three Placebo- Controlled Clinical Studies of 12 Weeks Treatment Duration, including Two Studies for Mildfil for Once Daily Us e for BPH and One Study for ED and BPH

Additional, less frequent adverse reactions ( < 1%) reported in the controlled clinical trials of Mildfil for BPH or ED and BPH included: gastroesophageal reflux disease, upper abdominal pain, nausea, vomiting, arthralgia, and muscle spasm.

Back pain or myalgia was reported at incidence rates described in Tables 1 through 4. In Mildfil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia associated with Mildfil treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. In general, pain was reported as mild or moderate in severity and resolved without medical treatment, but severe back pain was reported with a low frequency ( < 5% of all reports). When medical treatment was necessary, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective; however, in a small percentage of subjects who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all subjects treated with Mildfil for on demand use discontinued treatment as a consequence of back pain/myalgia. In the 1-year open label extension study, back pain and myalgia were reported in 5.5% and 1.3% of patients, respectively. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no evidence of medically significant underlying pathology. Incidence rates for Mildfil for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of Mildfil for once daily use, adverse reactions of back pain and myalgia were generally mild or moderate with a discontinuation rate of < 1% across all indications.

Across placebo-controlled studies with Mildfil for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with Mildfil (2.5% of patients).

Across all studies with any Mildfil dose, reports of changes in color vision were rare ( < 0.1% of patients).

The following section identifies additional, less frequent events ( < 2%) reported in controlled clinical trials of Mildfil for once daily use or use as needed. A causal relationship of these events to Mildfil is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful:

Body as a Whole - asthenia, face edema, fatigue, pain, peripheral edema

Cardiovascular - angina pectoris, chest pain, hypotension, myocardial infarction, postural hypotension, palpitations, syncope, tachycardia

Digestive - abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, GGTP increased, loose stools, nausea, upper abdominal pain, vomiting, gastroesophageal reflux disease, hemorrhoidal hemorrhage, rectal hemorrhage

Musculoskeletal - arthralgia, neck pain

Nervous - dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo Renal and Urinary