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Minister of Health of the Republic of Moldova
Directions for use
VITALIS 5 mg/dose
Oral spray, suspension
Vitalis 5 mg/dose
ICN ACTIVE INGREDIENTS
Active ingredient: tadalafilum 5 mg/dose
Other ingredients: Glycerol, macrogol 400, xanthan gum, benzoic acid, acesulfate potassium, polysorbate 80, flavor orange, vanillin, potassium sorbate, saccharin sodium, purifiend wather.
Oral spray, suspension
White suspension with specific smell and taste of orange and vanilla, homogeneous after strirring.
Pharmacotherapeutic group and ATC code
Drugs used in erectile dysfunction, G04BE08
Tadalafil is a selective inhibitor, reversible to phosphodiesterase type 5 (PDE5), specific to cyclic guanosine monophosphate (cGMP). When the sexual stimulation causes local release of nitric oxide, inhibitor of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum , resulting smooth muscle relaxation and inflow of blood into the penile tissues thereby producing an erection. Tadalafil has no effect in the absence of sexual stimulation.
Tadalafil is readily absorbed after oral administration and the mean maximum observed plasma concentration (Cmax ) is achieved at a median time of 10 minutes after administration. Absolute bioavailability of tadalafil following oral dosing has not been determined. The rate and extent of absorption of tadalafil are not influenced by food , so that preparation can be with or without food . Time of dosing (morning or evening ) had co clinically relevant effects on the rate and extend of absorption.
At therapeutic concentration 94% of the tadalafil in plasma is bound to protein. Protein binding is not affected by renal dysfunction . Less than 0.0005% of the administered dose appears in the semen of healthy subjects .
Tadalafil is predominantly metabolized by cytochrome P450 (CYP) 3A4 isoenzyme . The major circulating metabolite is the methylcatechol glucoronide . This metabolite is at least 13,000 times less than tadalafil for PDE5. Consequently , it is not expented to be clinically active at observed metabolite concentrations.
The mean oral clearance for tadalafil is 2.5 l/h and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites .
Linearity/not – linearity
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range from 5 mg to 20 mg , exposure(AUC) increases proportionally with dose. Steady state plasma concentrations are attained within 5 days of oncedaily administration. Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to the pharmacokinetics in subjects without erectile dysfunction.
Treatment of erectile dysfunction in adult males . For tadalafil to be effective, sexual stimulation is required .
DOSAGE AND METHOD OF ADMINISTRATION
Shake the bottle before use. Before the first use, press few times the spray device until the appearance of a dispersed flow. Administer spray sublingual or on lingual surface and mentain it in the oral cavity till the full absorbtion.
Use of adult men
Generally, the recommended dose is 10 mg, that is 2 sprayings (5 mg/spraying),taken prior to anticipated sexual activity with or without food. To the patients , to whom tadalafil 10 mg did not produce an adequate effect , 20 mg/4 sprayings might be tried. The drug can be administered at least 10 minutes before sexual activity . The maximum recommended dosing frequency is once per day and not more then 20 mg. Tadalafil 10 and 20 mg is intended for use prior to anticipated sexual activity and is not recommended for continuous daily use. To patients , whom Tadalafil is prescribed by the doctor for a continuous daily administration, the recommended dose is 5 mg per dey approximately at the same time of the day. Opportunity of continuous daily regimen should be reassessed periodically .
Use for elderly men
Dosage adjustments are not required in elderly patients .
Use in men with impaired renal function
No dosage adjustment is necessary for patients with mild to moderate impired renal function . For patients with severe renal impairment the maximum recommended dose in 10 mg. Daily dosing of tadalafil is not recommended in patients with severe renal impairment .
Use in men with impaired hepatic function
Vitalis recommended dose of 5 mg/dose is 10 mg taken with or without food, prior to anticipated sexual activity. There are limited clinical data on the safety of Tadalafil in patients with severe hepatic impairment (Child- Pugh Class C), if prescribed, the doctor will need to make a careful individual assessment of the benefit / risk ratio. No information on doses higher than 10 mg of Tadalafil in patients with hepatic impairment.
The use of men with diabetes mellitus
In diabetic patients dosage adjustments are not necessary.
Children and adolescents
Vitalis should not be used by person under the age of 18.
Adverse reactions are ranked by frequency, using MedDRA frequency convention:
Very common (>1/10)
Common (>1/100 and <1/10)
Uncommon (>1/1000, <1/100)
Rare (>1/10000, <1/1000)
Very rare (<1/10000)
Unknown (can not be estimated from available data).
Immune system disorders
Uncommon: hypersensitivity reactions
Nervous System Disorders
Rare: stroke, syncope, transient ischemic attacks, migraine, seizures, transient amnesia
Uncommon: blurred vision, sensations described as eye pain
Rare: visual field defect, eyelid edema, conjunctival hyperemia, anterior ischemic optic meuropathy, non – arteritic (NAION), retinal vascular occulusion
Ear and labyrinth disorders
Rare: Sudden deafness
Uncommon: tachycardia, palpitations
Rare: myocardial infarction, unstable angina, ventricular arrhythmia
Respiratory, thoracic and mediastinal disorders
Common: nasal congestion
Uncommon: dyspnea, epistaxis
Common: dyspepsia, gastro-oesophageal reflux
Uncommon: abdominal pain
Skin and subcutaneous tissue disorders
Uncommon: rash, hyperhidrosis (sweating)
Rare: urticarial, Stevens – Johnson syndrome, exfoliative dermatis
Musculoskeletal and connective tissue disorders
Common: back pain, myalgia, pain in extremity
Renal and urinary disorders
Reproductive system and breast disorders
Uncommon: bleeding from the penis, hematospermia
Rare: prolonged erection, priapism
General disorders and administration site
Uncommon: chest pain
Rare: facial swelling, sudden cardiac death
Not be used in men 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.
The following groups of patients with cardiovascular disease have not been included in clinical trials, and therefore the use of tadalafil is contraindicated in patients with:
· Myocardial infarction within the last 90 days.
· Unstable angina or angina occurring during sexual intercourse.
· Class 2 heart failure New York Heart Association (NYHA) or greater, failure in the last 6 month
· Uncontrolled arrhythmias, hypotension (<90/50 mmHg) or uncontrolled hypertension
· A stroke within the last 6 months
Tadalafil is contraindicated in patients who have loss of vision due to anterior ischemic optic neuropathy, non – arteritic (NAION), even though this episode was in connection or not with previous PDE5 inhibitor exposure.
Symptoms: Adverse reactions were similar to those seen at lower doses.
Treatment: In case of overdose, be taken, as needed, standard supportive measures.
WARNING AND SPECIAL PREAUTIONS FOE USE
Before initialing any treatment for erectile dysfunction, physicians should consider the cardiovascular status of patients, because the sexual activity is associated with degree of cardiac risk.
Tadalafil has vasodilator proprieties, resulting in mild and transient decreases in blood pressure and thus potentiate the hypotensive effects of nitrates.
It is not known if the preparation is effective in patients who have had surgery within the pelvic region or the radical prostatectomy without nerve preservation erection.
In some of the patients using concomitant alpha 1 blockers Vitalis 5 mg / dose can cause symptomatic hypotension. The combination of tadalafil and doxazosin is not recommended. Vitalis 5 mg / dose should be used caution in patients with:
· Anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s diseas) or in patients with conditions that predispose them to priapism (such as sickle cell anemia, multiple myeloma or leukemia).
· Using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin) as increased tadalafil exposure (AUC) for these drug combinations.
Use in pregnancy lactation
It is not indicated for use by women.
Influence on ability to drive and use machines.
Preparation effect on ability to drive and use machines is considered negligible. Although the frequency of reports of dizziness in tadalafil and placebo – treated groups in clinical trials was similar, before driving or operating machinery patients should know they react to Vitalis 5 mg/dose.
Effects of tadalafil on other drugs
In clinical studies, tadalafil (5 mg, 10 mg and 20 mg) was shown to augment the hypotensive effects. Therefore Vitalis administration in patients who are using any form of organic nitrate is contraindicated. In such circumstances, nitrates should only be administered under close medical supervision with apropiate hemodynamic monitoring.
Antihypertensive drugs (including calcium channel blockers)
Concomitant administration of doxazosin ( 4 and 8 mg daily) and tadalafil ( 5 mg daily dose and 20 mg single dose) significantly increase the hypotensive effect of this alpha – blocker. This effect lasts at least twelve hours and may symptomatic, including syncope. Therefore, such use is not recommended. In interaction studies to a limited number of healthy volunteers, these effects were not relative to administration of alfuzosin or tamsulosin. However, caution is needed when using tadalafil to patients who are taking any alpha –blocker therapy, and especially to the elder ones. Treatment should be initiated at the lowest dose and gradually adjusted.
Inhibitors of 5.allpha.-reductase
However, because it wasn’t conducted a formal drug-drug interaction to assess the effects of administration tadalafil with 5 alpha- reductase inhibitors (5-IAR) caution is needed in concomitant administration of tadalafil with 5 – IAR.
Substrates of CYP1A2 ( for example, theophylline )
When tadalafil 10 mg was administered with theophylline (non-selective phosphodiesterase inhibitor) in a clinical pharmacology study, there was no pharmacokinetic interaction manifested. The only pharmacodynamics effect was a small increase in heart rate ( 3.5 bpm). Although this effect is minor and had no clinical significance in this study, it should be considered when administering these drugs concomitantly.
Ethinykestradiol and terbutaline
Tadalafil has been desomnstrated to produce an increase in the oral bioavailability of ethinylestradiol; asimilar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.
Alcohol concentrations ( mean maximum blood alcohol levels of 0.08% ) were not affected by concomitant administration of tadalafil ( 10 mg or 20 mg ). In addition, no changes were found in tadalafil concentrations 3 hours after co-administration of alcohol. Effects of alcohol on cognitive function was not increased by tadalafil ( 10 mg ).
Drugs methabolized by cytochrome P450
Tadalafil os not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by CYP450 isoenzymes. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoenzymes, including CYP3A4, CYP1A2, CYP2D6, CYYP2E1, CYP2C9 and CYP2C19. CYP2C9 substrates ( e.g., R – warfarin )
Tadalafil ( 10 mg and 20 mg ) had no clinically significant effect on exposure (AUC) to S – warfarin or R – warfarin ( CYP2C9 substrate ) and did not affect changes in prothrombin time induced by warfarin.
Tadalafil ( 10 mg and 20 mg ) did not potentiate the increase of bleeding time caused by acetylic acid.
No specific interaction studies with andiabetic drugs.
Oral spray suspension, 5 mg/dose, 12 ml/48 doses in vial. 1 vial together with instructions for administration in cadboard box.
Store below 25°C.
Store in original package to protect from light and moisture.
Keep out of reach and sight of children!
Do not use after the expiry data shown on the pack.
Date of last revision of text March 2014.
NAME AND ADRESS
“Flumed – Farm” Ltd
Republic of Moldova