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NAME OF MEDICINAL PRODUCTS

EDRONAX 4 mg tablet
2. QUALITATIVE AND QUANTITATIVE COMPOSITION:

Reboxetine methanesulfonate 5.224 mg (equivalent to 4 mg Reboxetine base)

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4.1. Therapeutic indications

4.2. Posology and method of administration

: Posology / frequency and duration of: The

administrationrecommended therapeutic dose is 4 mg (8 mg / day) taken orally twice a day. The treatment can be initiated with a full therapeutic dose. After 3-4 weeks, this dose can be increased up to 10 mg per day in case of insufficient clinical response. The maximum daily dose should not exceed 12 mg. The minimum effective dose has not yet been determined.

Clinical efficacy is seen 14 days after starting treatment.

Method of:

Administration EDRONAX 4 mg tablet is used orally. Open or full.

Additional information on special populations:

Kidney / Liver failure: In patients with

renal or moderate to severe hepatic impairment, the initial dose should be 2 mg twice daily; this dose may be increased depending on patient tolerance.

4.4. Special warnings and precautions for use

Geriatric population:

4.3. Contraindications

4.4. Special warnings and precautions for use Since

clinically rare cases of epileptic seizures are observed, reboxetine should be given under strict supervision to people with known convulsive disease and discontinued use when seizures develop.

4.5. Interactions with other medicinal products and other forms of interaction In

clinical studies, the combined use of reboxetine with other antidepressants (tricyclics, MAO inhibitors, SSRPs and lithium) has not been evaluated.

As with all antidepressants, there were transitions to mania / hypomania. Bipolar patients are recommended to be monitored closely.

Clinical experience with reboxetine is limited in patients with severe comorbid systemic diseases. Close observation should be performed in patients with a history of prostate hypertrophy, glaucoma and a history of cardiac disease.

At doses above the maximum recommended dose, orthostatic hypotension was more common than the recommended dose range. Close monitoring is recommended when reboxetine is administered in combination with drugs known to have a blood pressure lowering effect.

Clinical experience with reboxetine in the long-term treatment of elderly patients is currently limited. In this population, average potassium levels decreased from 14 weeks of gestation; this decrease did not exceed 0.8 mmol / liter and the potassium levels never fell below the normal limits.

Use in children and adolescents under 18 years of age: _____

Antidepressant drugs and children up to 25 years of age, the possibility of suicidal thoughts or behaviors are likely to increase. For this reason, both the family and the doctor should be closely monitored by the patient for reasons such as suicide probability. In

clinical trials, suicidal behaviors (suicide attempts and suicidal thoughts) and hostile attitudes (mostly aggression, confrontation behavior and anger) were more common in children and adolescents treated with antidepressants than those treated with placebo. However, if a decision is made for treatment due to clinical need, the patient should be monitored carefully in order to detect suicidal symptoms. Moreover, there is no long-term safety data on growth, maturation and cognitive development in children and adolescents.

Depression; suicidal thoughts are associated with increased risk of self-harm and suicide (suicide related events). This risk continues until significant remission occurs. Since there will be no improvement for the first few weeks or longer of treatment, patients should be monitored closely until such an improvement is observed. General clinical experience suggests that suicide risk may increase in the early stages of recovery.

4.5. Interactions with other medicinal products and other forms of interaction

In vitro metabolism studies indicate that reboxetine is metabolised primarily by CYP3A4, the isozyme of cytochrome P450; reboxetine is not metabolized by CYP2D6. Therefore, it is expected that drugs that reduce the activity of CYP3A4 (ketoconazole, nefazodoi, erythromycin and fluvoxamine) will increase the plasma concentrations of reboxetine. In a study of healthy volunteers, it was found that the potent CYP3A4 inhibitor ketoconazole increases the plasma concentrations of reboxetine enantiomers by approximately 50%. On the other hand, low serum levels of reboxetine have been reported in combination with CYP3A4 inducing drugs such as phenobarbital and carbamazepine. Other CYP3A4 inducing drugs that can lower serum levels of reboxetine include, but are not limited to, bereferous phenytoin, rifampicin, and St John's Wort. Because of the narrow therapeutic margin of reboxetine, inhibition of elimination is one of the most important issues. Thus, reboxetine, azole group antifungal agents, macrolide antibiotics such as erythromycin, or fluvoxamine, such as fluvoxamine should not be given with drugs known to inhibit CYP3A4.

In vitro studies have shown that reboxetine does not inhibit the activity of cytochrome P450 isoenzymes such as CYP1A2, CYP2C9, CYP2C19 and CYP2E1. In compounds that are metabolized by these enzymes, pharmacokinetic interactions are not expected. In high concentrations, reboxetine inhibits CYP2D6, but the clinical significance of this observation is unknown. In vitro studies have shown that reboxetine inhibits CYP3A4 very little. The results of in vivo study suggest that there is no possibility of interaction with other drugs that are metabolized by these enzymes.

There was no significant pharmacokinetic interaction between reoxetine and lorazepam. Mild to moderate sleepiness and short-term orthostatic acceleration at heart rate were observed during co-administration in healthy volunteers. In an in vivo multi-dose study of healthy volunteers, no clinically significant interaction was observed between fluoxetine and reboxetine.

It is thought that reboxetine does not potentially potentiate the effect of alcohol on cognitive functions in healthy individuals. Considering

the potential risk (tyramine-like effect) based on the mechanisms of action, the simultaneous use of MAO inhibitors and reboxetine should be avoided. Concomitant use of reboxetine with other antidepressants (tricyclics, MAO inhibitors, SRs and lithium) was not evaluated in clinical trials.

The simultaneous use of ergot derivatives and reboxetine may result in an increase in blood pressure. Concomitant foods do not significantly affect the degree of absorption of reboxetine.

Although there is no data available from clinical trials, the possibility of hypokalemia should be considered with the simultaneous use of diuretics that cause potassium loss.

Additional information on special populations

4.6. Pregnancy and lactation

General advice

Pregnancy category: B

Women with childbearing potential / Contraception (Contraception)

There is no clinical data on exposure to pregnancies for Reboxetine.

Animal studies do not show any direct or indirect adverse effects with respect to pregnancy / embryonal / fetal development / birth or postnatal development (see section 5.3)

.

Pregnancy There

are no clinical research data on reboxetine use during pregnancy. However, a very limited number of post-marketing safety data on use in pregnancy has no adverse effect on reboxetine in pregnancy or in the health of the fetus / newborn.

Since there is no adequate and controlled study in pregnant women, the benefit / risk ratio should be evaluated.

Lactation

Reboxetine is known to pass into breast milk. The level of active substance in breast milk is expected to be very low, but there is not enough information to exclude the risk for the breastfed infant. When the potential benefits outweigh the risk to the child, reboxetine may be considered during breastfeeding.

Reproductive ability / Fertility

4.7. Effects on ability to drive and use machines

4.8. Adverse effects

Adverse effects have been reported in about 80% of reboxetine-treated patients and in about 70% of placebo-treated patients for eight weeks or less in placebo-controlled trials. The rate of drug withdrawal due to adverse effects was about 9% and 5%, respectively, in patients treated with reboxetine and placebo.

The more commonly seen adverse effects in patients treated with reboxetine compared to patients treated with placebo include dry mouth, constipation, insomnia, increased sweating, tachycardia, vertigo, urinary retention, and impotence. Impotence was mainly seen in patients treated with doses greater than 8 mg per day.

The only change in vital signs was tachycardia due to standing up. In adult patients, no permanent change in tachycardia was observed in ECG recordings during treatment with reboxetine.

In studies lasting more than 8 weeks, approximately 30% of patients treated with reboxetine and about 25% of patients treated with placebo had new adverse effects. There is no difference between the adverse effect profile of studies over eight weeks and the profiles of studies of eight weeks or less. Adverse effects seen when the drug is discontinued are rare; this occurred in 4% of the patients in the reboxetine group and 1% in the placebo group. The only side effect observed in the reboxetine-treated group was constipation.

Adverse effects during discontinuation were rare, occurring in approximately 4% of patients treated with reboxetine and 5% of those treated with placebo.

In clinical studies, more than 2100 patients received reboxetine and approximately 250 of them used reboxetine for at least 1 year.

Common adverse events that cause withdrawal of at least two times more studies in reboxetine than placebo include insomnia, dizziness, dry mouth, nausea, sweating, feeling of not completely emptying the bladder (men only), urinary retention (men only), and headache.

The following information relates to short-term controlled trials. The most common or widespread adverse events seen at least twice as much in reboxetine as compared to placebo are listed below.

The incidence of side effects and system are listed by organ class: Very common (> 1/10), widespread (> 1/100 to <1/10). uncommon (> 1 / 1,000 to <1/100), infrequently (> 1 / 10,000 to <1 / 1,000), very rare (<1 / 10,000), unknown (unpredictable from available data).

Nervous system disorders:

Very common: Insomnia

Common: Vertigo, akathisia, dizziness, sense of taste

Cardiac disorders:

perceptionspread: Tachycardia, palpitations, vasodilatation, postural hypotension

Eye disorders:

Common: Accommodation disturbance

Gastrointestinal disorders:

Very common: Dry mouth, constipation Extent of appetite or loss of appetite

Skin and subcutaneous tissue disorders:

Very common: Hyperhidrosis

Kidney and urinary disorders:

Common: Urinary incontinence, urinary tract infectionurinary tract infection

Reproductive system and breast disorders:

: Erectile dysfunction, pain during ejaculation , late ejaculation (only in males), testicular disorder-mostly pain (only in males)

General disorders and disorders related to the site of application:

Common: Urination In

addition, agitation, anxiety, irritability, aggressive behavior, hallucination, coldness in the extremities, nausea, vomiting, allergic dermatitis / rash, p There are spontaneous reports of aresthesia and hypertension.

4.4. Specific use warnings and precautions

Regarding long-term tolerability, 140 adult patients treated with reboxetine and placebo were enrolled in a long-term placebo-controlled trial. Adverse events occurred in 28% of patients treated with reboxetine and 23% in placebo-treated patients with long-term treatment and resulted in withdrawal from 4% * and% r of cases respectively. The risk of developing each adverse event with reboxetine and placebo is similar. Long-term studies did not show separate events that were not seen in short-term treatment.

6

In short-term controlled trials with patients with depression, there were no clinically significant differences between genders in terms of the frequency of symptoms associated with treatment; except for female patients treated with reboxetine (7% [59/847]), a higher percentage of male patients treated with reboxetine (31.4% [143/456]), as well as urological events (eg, bladder-free urinary incontinence and urinary frequency It has been reported. In contrast, the frequency of urological events was similar between male (5% [15/302]) and female (8.4% [37/440]) treated with placebo.

In the elderly population, the incidence of total adverse events as well as separate events were not higher than those reported above.

In pre-marketing clinical trials, newly reported symptoms and symptoms of sudden cessation of treatment were rare and less frequent in patients treated with reboxetine (4%) than those treated with placebo (6%). In post-marketing experience, several spontaneous reports of symptoms of withdrawal including headache, dizziness, irritability, and nausea have been reported, but in these reports a consistent case model of discontinuation of treatment with reboxetine was not evident.

In short-term depression studies where heart rate was assessed by ECG, reboxetine was associated with average increases in heart rate of 6 to 12 beats per minute compared to placebo.

In all short-term controlled studies of depression, the mean change in heart rate (heart rate per minute) for patients treated with reboxetine was 3, 6.4 and 2.9 for standing, sitting and supine positions, while 0, 0, and 0 for patients treated with placebo. It was -0.5. Again in the same studies, 0.8% of patients treated with reboxetine compared to 0.1% of patients treated with placebo discontinued the drug due to tachycardia.

Post-marketing experience The

following post-marketing events for reboxetine have been reported:

Metabolism and nutritional disorders

Unknown: Hyponatremia

Psychiatric disorders

Common: Agitation, anxiety Unknown: Hallucinations

Nervous system disorders:

prevalence: Paresthesia

Vascular disorders:

prevalence: Hypertension

Unknown: Peripheral coldness, Raynaud phenomenon

Gastrointestinal disorders:

Very common: Nausea Width: vomiting

Reproductive system and breast disorders:

Unknown: Testicular pain

General disorders and disorders related to the site of application:

4.9. Overdose and treatment

acute toxicity studies in animals show a very low toxicity with a wide margin of safety in terms of pharmacologically active doses. Clinical symptoms and cause of death have been associated with CNS stimulation (mostly convulsive symptoms).

For some cases, patients were given a higher dose (12-20 mg / day) than recommended doses during clinical trials over a period of several days to a few weeks. Newly reported complaints; postural hypotension, anxiety and hypertension. The elderly can be particularly sensitive to overdose.

In pre-marketing clinical trials, there are 5 reports of reboxetine overdose, either alone or in combination with other pharmacological agents. The amount of reboxetine taken was 52 mg in 1 patient as a single agent and 20 mg in combination with other agents in another patient. The remaining 3 patients swallowed an unknown amount of reboxetine. Five of 5 patients fully recovered. ECG abnormality, coma or convulsion has not been reported after overdose by reboxetine alone.

In post-marketing experience, several reports of overdose were taken in patients receiving reboxetine alone; none of them proved to be fatal. Non-fatal overdoses have been reported in patients receiving reboxetine up to 240 mg. Fatal overdose was reported in a patient who received reboxetine (doses unknown) in combination with amitriptyline.

In case of overdose, cardiac function and all fictitious findings should be monitored. General symptomatic support and / or emetic measures may be necessary.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Other antidepressants ATC code: N06AX18

Reboxetine is a highly selective and potent inhibitor of noradrenaline. It has only a weak effect on 5-HT reuptake and does not affect the recovery of dopamine.

As a result of inhibition of noradrenaline reuptake, increased noradrenaline levels in the synaptic interval and modification of noradrenergic transmission are among the most important mechanisms of action of known antidepressant drugs.

In vitro studies have shown that reboxetine has no significant affinity for adrenergic (α 1, α 2, β) and muscarinic receptors. Other antidepressant drugs (such as TCAs) have been reported to have cardiovascular, anticholinergic and sedative side effects due to their binding to such receptors. Reboxetine has no in vitro binding affinity for α 1 or 0 C 2 adrenoceptors, but functional interactions with α-adrenoceptors in high doses in vivo cannot be underestimated.

Reboxetine does not bind significantly to the histamine and dopamine receptors at therapeutic doses.

Following the administration of 1 and 3 mg of single doses of reboxetine in healthy volunteers, the symptoms of Central Nervous System (CNS) were observed, which was characterized by dose-dependent EEG modifications (decreased theta and fast beta waves in fronto-central leads) and improvement in performance (peg-board test). .

Over 5000 patients were included; A meta-analysis of reboxetine, placebo and active controlled trials was described as a 50% reduction in the Hamilton Depression Rating Scale scores. A significantly higher response was observed with reboxetine compared to placebo, (51.2% vs. 43.6%)

Response to reboxetine was not significant, although other active antidepressants (imipramine, fluoxetine, paroxetine, citalopram, dothiepin, venlafaxine) not as high, (59.7% versus 62.3%)

5.2. Pharmacokinetic properties

General characteristics

Absorption:

Approximately 130 mg / ml peak levels were reached within 2 hours after oral administration of 4 mg of single dose reboxetine to healthy volunteers. The available data indicate that absolute bioavailability is at least 60%. The plasma levels of reboxetine are reduced by a half-life with a half-life. Steady-state conditions were observed within five days.

Distribution:

Reboxetine is thought to be distributed to all body fluids. Reboxetine is bound to human plasma proteins (with significantly higher affinity to the α-acid glycoprotein than albumin) and 97% in young people and 92% in the elderly, without significantly correlating with drug concentration.

Bimetallization:

Reboxetine is metabolized to a large extent by oral administration of cytochrome P450 3A (CYP 3A4). The drug is metabolised by hydroxylation of the major ethoxyphenoxy ring and o-dealkylation and oxidation of the morpholine ring. In vitro studies have shown that CYP3A4, the isozyme of cytochrome P450, is primarily responsible for the metabolism of reboxetine. In vitro studies have shown that reboxetine has no effect on CYP1A2, CYP2C9, CYP2C19 and CYP2E1, which are isozymes of cytochrome P450. High concentrations of reboxetine inhibit CYP2D6 but the clinical significance of this condition is unknown. In vitro studies show that reboxetine is a very weak CYP3A4 inhibitor. Reboxetine inhibited CYP2D6 and CYP3A4, which had low binding affinities, but had no effect on in vivo clearance of drugs metabolized by these enzymes. Care must be taken when prescribing reboxetine with potent inhibitors of CYP3A4.

Elimination:

Approximately 78% of the dose is excreted in the urine. Although unchanged drug is predominant in the systemic circulation (70% of total radioactivity in terms of EAA), only 10% of the dose is excreted as unchanged drug in urine. These findings indicate that the general elimination of reboxetine occurs by biotransformation and that the metabolite excretion is limited by the formation of these metabolites. The major metabolic pathways identified are 2-O-dealkylation, hydroxylation of the ethoxyphenoxy ring, and partial or complete gluco or sulfo conjugation following the oxidation of the morpholine ring.

The drug is present as a racemic mixture (both enantiomers active in the experimental models, neither the chiral inversion nor the pharmacokinetic interaction between the enantiomers were observed): no mutual pharmacokinetic interactions between the chiral inversion or the enantiomers. The more potent SS enantiomer has approximately twice the plasma levels compared to its equivalent enantiomer and the urinary excretion is twice as high. No significant difference was observed between the terminal half-lives of these two enantiomers.

Linearity / non-linearity: The

pharmacokinetics of the clinically recommended dose ranges are linear.

Characteristic of patients:

5.3. Preclinical safety data

Reboxetine did not induce gene mutations in bacterial or mammalian cells in vitro, but induced chromosomal aberrations in human lymphocytes in vitro. Reboxetine did not cause DNA damage in yeast cells or rat hepatocytes in vitro. Reboxetine did not cause chromosomal damage in the in vivo mouse micronucleus test, but did not increase the incidence of tumors in carcinogenicity studies in mice and rats.

Hemosiderosis was reported only in rats in toxicity studies.

Studies in animals did not show any effect on teratogenic effect or overall reproductive performance. Doses that provide plasma concentrations in the therapeutic range for humans induce growth and development in the offspring of rats and prolonged behavioral changes.

In rats, reboxetine is passed into the milk.




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