Invida ODF (Films) Instructions for Use

Marketing Authorization Holder

Selvim, LLC (Russia)

Manufactured By

C.L. Pharm (Republic of Korea)

ATC Code

G04BE03 (Sildenafil)

Active Substance

Sildenafil (USAN)

Dosage Form

Invida ODF

Oral dispersible film 50 mg: 1, 2, 4, or 10 pcs.

Dosage Form, Packaging, and Composition

Oral dispersible films, from pale blue to bluish-green in color, thin, rectangular in shape.

Excipients: pullulan – 47 mg, sucralose – 7 mg, glycerol – 6.9 mg, macrogol 400 – 6.9 mg, aspartame (E951) – 4.82 mg, sodium bicarbonate – 4 mg, sodium hydroxide – 2.1 mg, peppermint leaf oil – 1 mg, colorant Kollicoat^® IR Brilliant Blue (copolymer of macrogol and polyvinyl alcohol, copovidone, titanium dioxide (E171), kaolin, sodium lauryl sulfate, colorant brilliant blue (E133)) – 0.05 mg, purified water – 0.17 ml.

1 film – sachet made of PET/Al/PE foil with laminated coating (1) – cardboard packs.
1 film – sachet made of PET/Al/PE foil with laminated coating (2) – cardboard packs.
1 film – sachet made of PET/Al/PE foil with laminated coating (4) – cardboard packs.
1 film – sachet made of PET/Al/PE foil with laminated coating (10) – cardboard packs.

Clinical-Pharmacological Group

Erectile dysfunction treatment drug. PDE5 inhibitor

Pharmacotherapeutic Group

Erectile dysfunction treatment agent – PDE5 inhibitor

Pharmacological Action

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

The realization of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum, and increased blood flow.

Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum but enhances the effect of NO by inhibiting PDE5, which is responsible for the breakdown of cGMP. Sildenafil is selective for PDE5 in vitro; its activity against PDE5 exceeds its activity against other known phosphodiesterase isoenzymes: PDE6 – by 10 times; PDE1 – by more than 80 times; PDE2, PDE4, PDE7-PDE11 – by more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDE3, which is of utmost importance since PDE3 is one of the key enzymes regulating myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in supine systolic blood pressure after taking sildenafil at a dose of 100 mg was 8.3 mm Hg, and diastolic pressure – 5.3 mm Hg. A more pronounced, but also transient, effect on blood pressure was noted in patients taking nitrates.

In some patients, 1 hour after taking sildenafil at a dose of 100 mg, a mild and transient impairment of the ability to distinguish shades of color (blue/green) was detected using the Farnsworth-Munsell 100 test. Two hours after taking the drug, these changes were absent. It is believed that the impairment of color vision is caused by the inhibition of PDE6, which is involved in the process of light transmission in the retina. Sildenafil does not affect visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter.

Pharmacokinetics

The pharmacokinetics of sildenafil in the recommended dose range are linear.

Absorption

After oral administration, it is rapidly absorbed. C_max in plasma when taken on an empty stomach is reached within 30-120 minutes (on average after 60 minutes), bioavailability averages 41% (25-63%). When taken with food, C_max decreases by 20-40%, and the time to reach C_max increases by 60 minutes. However, the extent of absorption does not change significantly (AUC decreases by 11%).

Distribution

The apparent V_d at steady state is 105 L. The binding of sildenafil and its main active metabolite to plasma proteins is about 96% of the administered dose and is not dose-dependent. Less than 0.0002% of the dose (average 188 ng) was found in semen 90 minutes after a single dose of sildenafil.

Metabolism

Sildenafil is mainly metabolized by the action of the isoenzymes CYP3A4 (main pathway) and CYP2C9 (secondary pathway) of hepatic microsomal isoenzymes. The main circulating active metabolite is the N-desmethyl metabolite, whose activity against phosphodiesterase is 50% of that of sildenafil, and its plasma concentration reaches 40% of the sildenafil concentration. The N-desmethyl metabolite undergoes further metabolism with a T_1/2 of 4 hours.

Elimination

The total clearance of sildenafil is 41 L/h, and the terminal T_1/2 is 3-5 hours. After oral administration, Sildenafil is excreted as metabolites, mainly via the intestine (about 80% of the orally administered dose) and, to a lesser extent, via the kidneys (about 13% of the orally administered dose).

Pharmacokinetics in special patient groups

In elderly patients (65 years and older), the clearance of sildenafil is reduced, and the concentration of free sildenafil and its active metabolite is increased by approximately 90% compared to patients aged 18-45 years. The concentration of unbound sildenafil in plasma is 40%.

In patients with mild or moderate renal impairment (creatinine clearance 30-80 ml/min), the pharmacokinetics of sildenafil do not change when taking 50 mg, and the C_max and AUC for the N-desmethyl metabolite increase by 73% and 126%, respectively. In patients with severe renal impairment (creatinine clearance less than 30 ml/min), the clearance of sildenafil is reduced, resulting in an increase in C_max and AUC by 88% and 100%, respectively, compared to patients with normal renal function of the same age group. C_max and AUC of the N-desmethyl metabolite increase by 79% and 200%, respectively.

In patients with liver cirrhosis (Child-Pugh classes A and B), the clearance of sildenafil is reduced, and C_max and AUC increase by 47% and 84%, respectively, compared to patients with normal liver function of the same age group. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Indications

• Treatment of erectile dysfunction characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.

Sildenafil is effective only with sexual stimulation.

ICD codes

Dosage Regimen

The drug Invida ODF is intended for oral administration and does not require water for swallowing; however, if desired, the drug can be taken with water.

The films should be taken approximately 1 hour before planned sexual activity.

When taking Invida ODF with food, the onset of action of the drug may be delayed compared to taking the drug on an empty stomach.

The recommended dose of Invida ODF is 50 mg (1 film).

Depending on efficacy and tolerability, the dose of the drug can be increased to 100 mg. The maximum single dose is 100 mg once/day.

Alcohol consumption can temporarily impair the ability to achieve an erection. To get the maximum benefit from the drug, it is not recommended to abuse alcohol before starting sildenafil.

In elderly patients, dose adjustment is not required.

In patients with mild or moderate renal impairment (creatinine clearance 30-80 ml/min), dose adjustment is not required. In patients with severe renal impairment (creatinine clearance less than 30 ml/min), the use of the drug must be agreed with the attending physician.

In patients with mild and moderate hepatic impairment, the use of the drug must be agreed with the attending physician.

Patients receiving concomitant treatment with other inhibitors of the CYP3A4 isoenzyme (erythromycin, saquinavir, ketoconazole, itraconazole) should consult a doctor before starting the drug.

To reduce the risk of orthostatic hypotension in patients taking alpha-adrenergic blockers, sildenafil should be started only after their condition has stabilized on alpha-blocker therapy and after consultation with the attending physician.

Method of administration

Important: do not touch the film with wet hands.

1. Take the sachet, find the mark with the inscription “open” on one of the short sides.

2. Carefully open the sachet by pulling the free edges in opposite directions, separating them from each other, and release the film.

3. With dry fingers, take the film from the sachet and place it in the oral cavity – on the tongue, after which the film will quickly dissolve in saliva, which can be easily swallowed.

Adverse Reactions

Side effects are classified according to the following frequency: very common (at least 10%); common (at least 1%, but less than 10%); uncommon (at least 0.1%, but less than 1%); rare (at least 0.01%, but less than 0.1%); very rare (less than 0.01%, including isolated cases).

Nervous system disorders very common – headache; common – dizziness; uncommon – drowsiness, hypoesthesia; rare – cerebrovascular accident, syncope; frequency unknown – transient ischemic attack, seizures, including recurrent.

Eye disorders common – visual impairment, color vision disturbance; uncommon – conjunctival lesion, lacrimation disorder; frequency unknown – anterior ischemic optic neuropathy, retinal vascular occlusion, visual field defects.

Ear and labyrinth disorders uncommon – vertigo, tinnitus; rare – deafness.

Cardiac and vascular disorders common – “flushing”; uncommon – palpitations, tachycardia; rare – increase or decrease in blood pressure, myocardial infarction, atrial fibrillation; frequency unknown – ventricular arrhythmia, unstable angina, sudden death.

Respiratory, thoracic and mediastinal disorders common – nasal congestion; rare – epistaxis.

Gastrointestinal disorders common – dyspepsia; uncommon – vomiting, nausea, dry oral mucosa.

Reproductive system and breast disorders uncommon – hematospermia, penile bleeding; frequency unknown – priapism, prolonged erection.

Immune system disorders uncommon – skin rash; frequency unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

General disorders and administration site conditions rare – chest pain, fatigue.

Contraindications

• Hypersensitivity to sildenafil or any other component of the drug;
• With continuous or intermittent use of nitric oxide donors (such as amyl nitrite), organic nitrates or nitrites in any dosage forms, since Sildenafil enhances the hypotensive effect of nitrates;
• Use in patients for whom sexual activity is undesirable (including those with severe cardiovascular diseases such as unstable angina, severe heart failure, life-threatening arrhythmias, arterial hypotension (BP less than 90/50 mm Hg));
• Myocardial infarction or cerebrovascular accident within the last 6 months;
• Hereditary degenerative retinal diseases, including retinitis pigmentosa (a small proportion of such patients have a genetic disorder of retinal PDE);
• Hepatic insufficiency;
• Severe chronic renal failure;
• According to the registered indication, the drug is not intended for use in women and children under 18 years of age;
• Concomitant use of other medicinal products for the treatment of erectile dysfunction;
• Concomitant use of ritonavir;
• Phenylketonuria.

With caution

• Arterial hypertension (BP more than 170/100 mm Hg);
• Left ventricular outflow tract obstruction, including aortic stenosis, hypertrophic obstructive cardiomyopathy;
• Anatomical deformation of the penis (angulation, cavernous fibrosis, or Peyronie’s disease);
• Diseases predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia);
• Diseases accompanied by bleeding;
• Exacerbation of gastric and duodenal ulcers;
• With simultaneous use of alpha-adrenergic blockers (risk of orthostatic hypotension);
• Patients with vision loss in one eye due to non-arteritic anterior ischemic optic neuropathy (regardless of whether this occurred due to taking a PDE5 inhibitor or not).

Use in Pregnancy and Lactation

According to the registered indication, the drug is not intended for use in women.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic insufficiency.

Use in Renal Impairment

The use of the drug is contraindicated in severe chronic renal failure.

In patients with mild or moderate renal impairment (creatinine clearance 30-80 ml/min), dose adjustment is not required.

Pediatric Use

According to the registered indication, the drug is not intended for use in children and adolescents under 18 years of age.

Geriatric Use

In elderly patients, dose adjustment is not required.

Special Precautions

To diagnose erectile dysfunction, determine its possible causes, and select adequate treatment, it is necessary to collect a complete medical history and conduct a thorough physical examination.

Erectile dysfunction treatments should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia).

Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the cardiovascular system. Drugs intended for the treatment of erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable (see section “Contraindications”).

Cardiovascular complications

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as serious cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) have been reported, which had a temporal relationship with the use of sildenafil. Most of these patients, but not all, had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the reported adverse events and the mentioned or other factors.

Hypotension

Sildenafil has a systemic vasodilatory effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before prescribing Invida ODF, the doctor should carefully assess the risk of possible undesirable manifestations of the vasodilatory effect in patients with relevant diseases, especially during sexual activity. Increased susceptibility to vasodilators is observed in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe impairment of blood pressure regulation by the autonomic nervous system.

Since the combined use of sildenafil and alpha-adrenergic blockers can lead to symptomatic hypotension in some sensitive patients, Sildenafil should be prescribed with caution to patients taking alpha-adrenergic blockers. To minimize the risk of postural hypotension in patients taking alpha-adrenergic blockers, Sildenafil should be started only after hemodynamic stabilization has been achieved in these patients. The advisability of reducing the initial dose of sildenafil should be considered. In addition, the doctor should inform patients about what actions to take in case of symptoms of postural hypotension.

Visual impairment

If a visual defect occurs, you should immediately consult a doctor.

Hearing impairment

In some post-marketing and clinical studies using all PDE5 inhibitors, including Sildenafil, sudden decrease or loss of hearing has been reported in patients. However, in most cases, these patients had risk factors for the development of this pathology, and no correlation was found between the use of PDE5 inhibitors and sudden decrease or loss of hearing. The patient should be warned that in case of sudden decrease or loss of hearing, it is necessary to discontinue sildenafil therapy and immediately consult a doctor.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside (a nitric oxide donor) on human platelets in vitro. There is no information on the safety of sildenafil in patients with internal bleeding or active peptic ulcer, so the drug should be used with caution.

Use with other agents for the treatment of erectile dysfunction

The safety and efficacy of sildenafil in combination with other agents for the treatment of erectile dysfunction have not been studied, therefore the use of such combinations is not recommended.

Effect on the ability to drive vehicles and machinery

Since a decrease in blood pressure and the development of visual disturbances are possible, one should be attentive to the individual effect of the drug, especially at the beginning of treatment and when changing the dosage regimen, and exercise caution when driving and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

With a single dose of the drug up to 800 mg, adverse events were comparable to those with lower doses, but occurred more frequently.

Treatment symptomatic therapy. Hemodialysis is not effective because Sildenafil is highly bound to plasma proteins and is not excreted in the urine.

Drug Interactions

Sildenafil is metabolized primarily in the liver by the CYP3A4 (major pathway) and CYP2C9 isoenzymes, therefore inhibitors of these isoenzymes may decrease, and inducers respectively increase, the clearance of sildenafil.

Concomitant use of CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine) has been shown to decrease the clearance of sildenafil.

Cimetidine (800 mg), a non-specific inhibitor of CYP3A4, when taken concomitantly with sildenafil (50 mg), causes a 56% increase in plasma concentration of sildenafil.

A single dose of sildenafil 100 mg co-administered with erythromycin, a specific inhibitor of CYP3A4 (erythromycin 500 mg twice daily for 5 days), at steady-state erythromycin concentrations, resulted in a 182% increase in sildenafil AUC.

When sildenafil (single 100 mg dose) was co-administered with saquinavir, which is both an HIV protease inhibitor and a CYP3A4 inhibitor (saquinavir 1200 mg three times daily), at steady-state saquinavir concentrations, the C_max of sildenafil increased by 140%, and AUC increased by 210%. Sildenafil did not affect the pharmacokinetic parameters of saquinavir. More potent inhibitors of the CYP3A4 isoenzyme, such as ketoconazole or itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.

Concomitant administration of sildenafil (single 100 mg dose) and ritonavir, an HIV protease inhibitor and a potent inhibitor of cytochrome P450 isoenzymes (ritonavir 500 mg twice daily), at steady-state ritonavir concentrations, increased the C_max of sildenafil by 300% (4-fold), and AUC by 1000% (11-fold). After 24 hours, the plasma concentration of sildenafil was approximately 200 ng/ml (compared to 5 ng/ml with sildenafil alone), which is consistent with the known pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P450 substrates. Sildenafil did not affect the pharmacokinetics of ritonavir. Concomitant use of sildenafil with ritonavir is not recommended.

Grapefruit juice, a weak inhibitor of CYP3A4, may moderately increase plasma concentrations of sildenafil.

A single dose of an antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

Inhibitors of CYP2C9 (such as tolbutamide, warfarin), CYP2D6 (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not affect the pharmacokinetic parameters of sildenafil. Concomitant administration of azithromycin (500 mg/day for 3 days) did not affect the AUC, C_max, T_max, elimination rate constant and T_1/2 of sildenafil or its main circulating metabolite.

Nicorandil is a hybrid of a nitrate and a potassium channel activator. Due to the nitrate component, nicorandil can interact seriously with sildenafil and lead to severe arterial hypotension.

Effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC₅₀ >150 µM). It is unlikely that Sildenafil will affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates, both during long-term use and during acute use. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

When doxazosin (4 and 8 mg) and sildenafil (25, 50 and 100 mg) were co-administered in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional reduction in supine systolic/diastolic blood pressure was 7/7, 9/5 and 8/4 mm Hg, respectively, and in the standing position – 6/6, 11/4 and 4/5 mm Hg, respectively. Rare cases of symptomatic postural hypotension manifested as dizziness (without fainting) have been reported in such patients. In individual sensitive patients receiving alpha-blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

No signs of significant interaction between sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9, were found.

Sildenafil 100 mg did not affect the pharmacokinetic parameters of HIV protease inhibitors at their steady-state concentrations, such as saquinavir and ritonavir, which are also substrates of CYP3A4.

Sildenafil (50 mg) does not cause additional prolongation of bleeding time when taken with acetylsalicylic acid (150 mg).

Sildenafil (50 mg) does not enhance the hypotensive effect of ethanol in healthy volunteers with a maximum mean blood ethanol level of 80 mg/dL.

In patients with arterial hypertension, no signs of interaction between sildenafil (100 mg) and amlodipine were found. The mean additional reduction in supine blood pressure was: systolic – by 8 mm Hg, diastolic – by 7 mm Hg.

The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years. The drug should not be used after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.