Deltiba

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DELTYBA® (DELTYBA®)

Composition:

Active substance: delamanid;

One film-coated tablet contains 50 mg of delamanid;

Excipients: tablet core – hypromellose phthalate, povidone (K-25), alpha-tocopherol, microcrystalline cellulose, sodium starch glycolate (type A), carmellose calcium, colloidal hydrated silicon dioxide, magnesium stearate, lactose monohydrate; coating – hypromellose, macrogol 8000, titanium dioxide, talc, iron oxide (yellow) (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, slightly convex film-coated tablets with bevel, of yellow color, marked with "DLM" and "50" on one side.

Pharmacotherapeutic group. Antibacterials for systemic use. Antituberculosis agents. Delamanid.

ATC code J04A K06.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The pharmacological mechanism of action of delamanid is related to the inhibition of synthesis of mycobacterial cell wall components – methoxy- and keto-mycolic acids. Delamanid metabolites identified so far do not exhibit antimycobacterial activity.

Activity against specific pathogens

Delamanid has no activity in vitro against any bacterial species other than M. tuberculosis.

Resistance

Mutation in one of the five genes encoding coenzyme F420 is considered to be the mechanism underlying the development of mycobacterial resistance to delamanid. In vitro, the frequency of spontaneous development of mycobacterial resistance to delamanid due to gene mutation is similar to that of spontaneous resistance to isoniazid and higher than that of spontaneous resistance to rifampicin.

Development of resistance to delamanid during treatment has been observed (see section "Special precautions"). There is no cross-resistance between delamanid and any other currently used antituberculosis agents, except pretomanid. In vitro studies have demonstrated development of cross-resistance with pretomanid. This is likely due to the fact that both delamanid and pretomanid are activated via the same pathway.

Criteria for interpretation of susceptibility testing

When using 7H11 agar medium for susceptibility testing, the following epidemiological cutoff values (ECOFF) and interpretive criteria for delamanid are recommended:

ECOFF: 0.016 mg/L;

resistance breakpoints: S ≤ 0.016 mg/L; R > 0.016 mg/L;

S – susceptible; R – resistant.

Clinical study data

In the first double-blind, placebo-controlled trial, 161 patients with multidrug-resistant tuberculosis (MDR-TB) received delamanid 100 mg twice daily for 8 weeks in combination with a World Health Organization (WHO)-recommended individualized optimized background regimen (OBR). Table 1 presents comparative data on sputum culture conversion at 2 months (i.e., absence of growth of Mycobacterium tuberculosis in patients with positive baseline sputum cultures) in patients receiving delamanid + OBR versus those receiving placebo + OBR.

Table 1

MGIT® – liquid growth medium for mycobacteria with a fluorescent component in test tubes; n – number of patients with sputum conversion within 2 months; N – total number of patients in the group.

In a second double-blind, placebo-controlled clinical trial, delamanid was administered at a dose of 100 mg twice daily for 2 months, followed by 200 mg once daily for 4 months, in combination with a background regimen (BR). The study included 511 patients. The median time to sputum conversion in the group of patients receiving delamanid plus BR was 51 days, compared to 57 days in the placebo group. The proportion of patients achieving sputum conversion by month 6 was 87.6% (198 out of 226 patients) in the delamanid group and 86.1% (87 out of 101 patients) in the placebo group. The study design assumed that all missed sputum samples were considered positive. Therefore, the study results were analyzed twice: by last observation carried forward and by a special sensitivity analysis. The second analysis used a method whereby a sputum test result was considered negative only if both the preceding and subsequent results were negative; otherwise, the sputum test was considered positive. The study results showed that the median time to sputum conversion in the delamanid group was 13 days shorter than in the placebo group (p = 0.0281 and 0.0052 for the respective analyses).

Paediatric patients (6–18 years of age)

The pharmacokinetics, safety, and efficacy of delamanid in combination with a background treatment regimen in children were evaluated in study 242-12-232 (10-day pharmacokinetics), followed by study -233 (pharmacokinetics, efficacy, and safety). Both studies were uncontrolled, open-label trials involving 37 patients with a mean age of 4.55 years (range: 0.78 to 17.60 years); 25 participants (67.6%) were of Asian origin and 19 (51.4%) were female.

Paediatric patients were grouped into four categories:

Group 1: children aged 12 to 17 years (7 patients); Group 2: children aged 6 to 11 years (6 patients); Group 3: children aged 3 to 5 years (12 patients); Group 4: children aged 0 to 2 years (12 patients). The overall mean baseline body weight of patients was 19.5 kg, with mean body weights in Groups 1, 2, 3, and 4 being 38.4, 25.1, 14.8, and 10.3 kg, respectively.

All patients had confirmed or probable MDR-TB and were to receive 26 weeks of delamanid + BR, followed by BR alone, in accordance with WHO recommendations. Patients in Group 1 and Group 2 received delamanid in the form of film-coated tablets. Group 1 received a dose of 100 mg delamanid twice daily, while Group 2 received 50 mg delamanid twice daily. This dosing regimen was higher than the recommended weight-based dosing for paediatric patients.

Patients in Group 3 and Group 4 received delamanid in a different pharmaceutical form and strength.

A population pharmacokinetic analysis was performed based on data from two clinical studies to determine the dosing regimen for paediatric patients that would provide delamanid exposure similar to that observed in adult MDR-TB patients.

This medicinal product is authorized under a "conditional approval" scheme in the European Union. This means that additional evidence for this medicinal product is expected. The European Medicines Agency will review new information on this medicinal product at least annually, and this Product Information Leaflet will be updated as necessary.

Pharmacokinetics.

Absorption

The oral bioavailability of delamanid increases approximately 2.7-fold when administered with food (standard meal) compared to administration in the fasted state. Peak plasma concentrations are reached approximately 4 hours after dosing, regardless of food intake.

Linearity/non-linearity

Plasma exposure to delamanid increases with dose, but not in a linear manner.

Distribution

The extent of delamanid binding to plasma proteins is high (≥ 99.5%). Delamanid is characterized by a large volume of distribution (Vz/F = 2100 L).

Biotransformation

Delamanid is primarily metabolized in plasma by albumin, and to a lesser extent by CYP3A4. The complete metabolic profile of delamanid in humans has not yet been fully established. Therefore, if significant unknown metabolites are identified, the potential for drug-drug interactions with delamanid when co-administered with other drugs may change. Identified metabolites do not possess antimycobacterial activity but contribute to QTc interval prolongation to varying degrees (primarily metabolite DM-6705). Concentrations of known metabolites progressively increase until steady state is reached after 6–10 weeks.

Elimination

The elimination half-life of delamanid from plasma is 30–38 hours. Delamanid is not excreted in urine.

Pharmacokinetics in special patient populations

Children

When delamanid therapy was administered according to the recommended dosing regimen in children weighing ≥10 kg, plasma exposure was comparable to that observed in adult patients.

Patients with renal impairment

Less than 5% of an orally administered dose of delamanid is excreted in urine. Mild renal impairment (50 ml/min < creatinine clearance < 80 ml/min) is unlikely to affect delamanid exposure. Therefore, no dose adjustment is necessary for patients with mild or moderate renal impairment. It is unknown whether delamanid and its metabolites are removed by haemodialysis or peritoneal dialysis.

Patients with hepatic impairment

No dose adjustment is required for patients with mild hepatic impairment. Delamanid is not recommended for patients with moderate or severe hepatic impairment.

Elderly patients (aged 65 years and older)

Patients aged 65 years and older were not included in clinical trials of delamanid.

Preclinical safety data

Preclinical data reveal no specific hazard to humans based on conventional genotoxicity and carcinogenic potential studies. Delamanid and/or its metabolites may affect cardiac repolarization by blocking hERG potassium channels. Foamy macrophages were observed in lymphoid tissues of various organs in dogs during repeat-dose toxicity studies. This finding was shown to be partially reversible; the clinical significance of this observation is unknown. Repeat-dose toxicity studies in rabbits revealed an inhibitory effect of delamanid and/or its metabolites on vitamin K-dependent blood coagulation. Embryo-fetal toxicity was observed in rabbits at maternally toxic doses. Pharmacokinetic data from animal studies showed excretion of delamanid/metabolites into breast milk. In lactating rats, the Cmax of delamanid in breast milk was 4 times higher than in blood. Juvenile toxicity studies in rats showed findings consistent with those observed in adult animals.

Clinical characteristics.

Indications.

Deltyba®, film-coated tablets, 50 mg, is indicated as part of an appropriate combination regimen for the treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB) in adult patients (aged 18 years and older) and children with body weight of at least 30 kg, when alternative treatment regimens cannot be used due to resistance or intolerance (see sections "Dosage and administration", "Special precautions", and "Pharmacodynamics").

Attention should be paid to official guidelines regarding appropriate use of antibacterial agents.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Serum albumin level < 2.8 g/dL (information on use in patients with serum albumin levels ≥ 2.8 g/dL, see section "Special precautions").

Concomitant use of delamanid with medicinal products that are strong inducers of CYP3A4 (e.g., carbamazepine).

Interaction with other medicinal products and other forms of interaction.

The complete metabolic profile of delamanid and its elimination pathways have not yet been fully characterized (see sections "Special precautions" and "Pharmacokinetics").

Effect of other medicinal products on Deltyba®

Cytochrome P450 3A4 inducers

In clinical drug interaction studies involving healthy volunteers, exposure to delamanid was reduced by up to 45% over 15 days when co-administered with the strong cytochrome P450 (CYP) 3A4 inducer rifampicin (300 mg daily) and delamanid (200 mg daily). No clinically significant reduction in delamanid exposure was observed when delamanid 100 mg twice daily was co-administered with the weak inducer efavirenz 600 mg daily for 10 days.

Antiretroviral agents

In clinical drug interaction studies, healthy volunteers received delamanid alone (100 mg twice daily) and in combination with tenofovir disoproxil (245 mg daily), lopinavir/ritonavir (400/100 mg daily) for 14 days, or efavirenz (600 mg daily) for 10 days.

When co-administered with antiretroviral agents such as tenofovir disoproxil and efavirenz, delamanid exposure was unchanged (< 25% difference), but slightly increased when co-administered with the antiretroviral agent containing lopinavir/ritonavir. Delamanid administered in combination with anti-HIV drugs (tenofovir disoproxil, lopinavir/ritonavir, and efavirenz) did not affect the pharmacokinetics of these agents.

Effect of the medicinal product Deltyba® on other medicinal products

Antituberculosis agents

In clinical drug interaction studies, healthy volunteers received delamanid alone (200 mg daily) and in combination with rifampicin/isoniazid/pyrazinamide (300/720/1800 mg daily) or ethambutol (1100 mg daily) for 15 days. There was no effect on exposure to concomitant antituberculosis agents (rifampicin [R]/isoniazid [H]/pyrazinamide [Z]). However, concomitant administration with delamanid significantly increased ethambutol plasma trough concentrations (by approximately 25%), although the clinical significance of this finding is unknown.

MEDICINAL PRODUCTS THAT MAY PROLONG THE QTc INTERVAL

Delamanid should be administered with caution to patients who are already receiving medicinal products that may prolong the QTc interval (see section "Special precautions"). Studies on the combined use of moxifloxacin and delamanid in patients with MDR-TB have not been conducted. Moxifloxacin is not recommended for patients receiving delamanid.

Effect of delamanid on CYP450 isoenzymes in in vitro studies

In vitro studies have shown that delamanid does not inhibit CYP450 isoenzymes. In vitro studies demonstrated that delamanid and its metabolites do not affect the transporter proteins MDR1 (P-glycoprotein), BCRP, OATP1, OATP3, OCT1, OCT2, OATP1B1, OATP1B3, and BSEP at concentrations approximately 5–20 times higher than the Cmax at steady state. However, considering that delamanid concentrations in the intestinal lumen may substantially exceed these levels, there is a potential for delamanid to affect these transporter proteins.

Special precautions for use

There are no data on the use of delamanid for more than 24 consecutive weeks (see section "Dosage and administration").

There are no clinical data on the use of delamanid for the treatment of:

• extrapulmonary tuberculosis (e.g. tuberculosis of the central nervous system, bones);
• infections caused by other species of mycobacteria, except for the M. tuberculosis complex;
• latent infection caused by M. tuberculosis.

There are no clinical data on the use of delamanid as part of combination therapy for tuberculosis caused by drug-susceptible M. tuberculosis strains.

Resistance to delamanid

Delamanid should be used exclusively as part of an appropriate multidrug-resistant tuberculosis (MDR-TB) combination regimen according to WHO recommendations in order to prevent the development of resistance to delamanid.

QT interval prolongation

QT interval prolongation has been observed in patients receiving delamanid therapy. The QT interval increases gradually during the first 6–10 weeks of treatment and then remains stable.

QTc prolongation is clearly correlated with plasma concentrations of the main metabolite DM-6705. Accordingly, plasma albumin and CYP3A4 regulate the formation and metabolism of DM-6705 (see below "Special warnings").

General recommendations

It is recommended to perform electrocardiograms (ECG) before starting treatment and monthly thereafter until the end of delamanid administration. If QTcF > 500 ms is observed before the first dose of delamanid or during treatment, delamanid therapy should not be initiated or should be discontinued. If during delamanid treatment the QT interval exceeds 450 ms (in males) or 470 ms (in females), such patients should undergo more frequent ECG monitoring. Before starting delamanid therapy, serum electrolytes (e.g. potassium) should be assessed and any abnormalities corrected.

Special warnings

Cardiac risk factors

Initiation of delamanid therapy in patients with the following risk factors should be avoided unless the expected benefit outweighs the potential risk. In such cases, very frequent ECG monitoring is required throughout the entire period of delamanid use.

• Congenital QTc prolongation or any clinical condition that may lead to QTc prolongation, or QTc > 500 ms.

  • History of clinically significant arrhythmias or clinically relevant bradycardia.
  • Cardiovascular diseases that may predispose to arrhythmias, such as severe arterial hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy), or congestive heart failure with reduced left ventricular ejection fraction.

• Electrolyte imbalances, particularly hypokalemia, hypocalcemia, or hypomagnesemia.

• Concomitant use of medicinal products capable of prolonging the QTc interval. These include, among others:

• Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol).

• Neuroleptics (e.g. phenothiazines, sertindole, sulpiride, chlorpromazine, haloperidol, mesoridazine, pimozide, thioridazine), antidepressants.

• Certain antimicrobial agents, including:

• macrolides (e.g. erythromycin, clarithromycin);

• moxifloxacin, sparfloxacin (for information on concomitant use with other fluoroquinolones, see section "Special precautions for use");

• bedaquiline;

• triazole-derived antifungal agents;

• pentamidine;

• saquinavir.

• Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine).

• Certain antimalarial agents capable of prolonging the QT interval (e.g. halofantrine, quinine, chloroquine, artesunate/amodiaquine, dihydroartemisinin/piperaquine).

• Cisapride, droperidol, domperidone, bepridil, difeminal, probucol, levometadil, methadone, vinca alkaloids, arsenic trioxide.

Hypoalbuminemia

In a clinical study, hypoalbuminemia was associated with an increased risk of QTc prolongation in patients receiving delamanid. Delamanid is contraindicated in patients with albumin levels < 2.8 g/dL (see section "Contraindications").

Patients who start delamanid therapy with serum albumin levels < 3.4 g/dL or whose albumin levels decrease to this level during treatment require frequent ECG monitoring throughout delamanid therapy.

Concomitant use with strong CYP3A4 inhibitors

Concomitant use of delamanid with a strong CYP3A4 inhibitor (lopinavir/ritonavir) resulted in a 30% increase in exposure to the metabolite DM-6705, which was associated with QTc prolongation. Therefore, if delamanid must be co-administered with a strong CYP3A4 inhibitor, frequent ECG monitoring is recommended throughout the treatment period.

Concomitant use of delamanid with fluoroquinolones

All cases of QTcF prolongation exceeding 60 ms occurred during concomitant use of fluoroquinolones. Therefore, if treatment of MDR-TB cannot be managed without concomitant use of these agents, very frequent ECG monitoring is recommended throughout delamanid therapy.

Hepatic impairment

The medicinal product Deltyba® is not recommended for use in patients with moderate or severe hepatic impairment (see sections "Dosage and administration" and "Pharmacokinetics").

Renal impairment

There are no data on the use of delamanid in patients with severe renal impairment. The medicinal product Deltyba® is not recommended for use in patients with severe renal impairment (see sections "Dosage and administration" and "Pharmacokinetics").

Paradoxical drug reaction

During the post-marketing period, cases of paradoxical drug reactions have been reported during delamanid use, characterized by clinical or radiological worsening of existing lesions or development of new lesions in patients who previously showed positive response to appropriate antimycobacterial therapy. Paradoxical drug reactions are often transient and should not be interpreted as lack of treatment response. In suspected cases, it is recommended to continue the planned combination therapy and, if necessary, initiate symptomatic treatment to suppress an exaggerated immune response (see section "Adverse reactions").

Excipients

Deltyba® tablets contain lactose. The medicinal product should not be administered to patients with rare hereditary conditions such as galactose intolerance, absolute lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of delamanid in pregnant women are limited. Animal studies have shown that delamanid has reproductive toxicity (see section "Preclinical safety data"). Deltyba® should not be administered to pregnant women or women of childbearing potential who are not using reliable contraception.

Breastfeeding

It is unknown whether delamanid or its metabolites are excreted in human breast milk. According to available pharmacokinetic data in animals, delamanid and/or its metabolites are excreted in breast milk (see section "Preclinical safety data"). As a potential risk to the breastfed infant cannot be excluded, breastfeeding is not recommended during treatment with Deltyba®.

Fertility

Deltyba® had no effect on fertility in male or female animals (see section "Preclinical safety data"). There are no clinical data on the effect of delamanid on human reproductive function.

Ability to influence the speed of reactions when driving or operating machinery

Deltyba® may have a moderate influence on the ability to drive or operate machinery. Patients should therefore be advised to refrain from operating machinery if they experience adverse reactions that may affect such activities (e.g. headache, which is very common, and tremor, which is common).

Method of Administration and Dosage

Treatment with delamanid should be initiated and monitored only by physicians experienced in the management of multidrug-resistant tuberculosis caused by Mycobacterium tuberculosis.

Delamanid must be used exclusively as part of an appropriate combined regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) (see sections "Special Instructions" and "Pharmacodynamics"). According to WHO recommendations, after completion of the 24-week delamanid treatment period, anti-tuberculosis therapy should be continued using an appropriate combined regimen.

It is recommended that delamanid administration be directly observed by a healthcare provider.

Method of Administration

For oral use.

Delamanid should be taken with food.

Dosage

The recommended dose for adult patients is 100 mg twice daily for 24 weeks.

Elderly patients (aged 65 years and older)

There are no data available on the use of DELTYBA® in elderly patients.

Patients with renal impairment

Dose adjustment is not required in patients with mild or moderate renal impairment. There are no data on the use of delamanid in patients with severe renal impairment. DELTYBA® is not recommended for use in patients with severe renal impairment (see sections "Special Instructions" and "Pharmacokinetics").

Patients with hepatic impairment

Dose adjustment is not required in patients with mild hepatic impairment. Delamanid is not recommended for use in patients with moderate or severe hepatic impairment (see sections "Special Instructions" and "Pharmacokinetics").

Children

The recommended dose for children with body weight ≥50 kg is 100 mg twice daily for 24 weeks.

For children with body weight ≥30 kg but <50 kg, the recommended dose is 50 mg twice daily for 24 weeks.

The safety and efficacy of delamanid in children with body weight from 10 kg to 30 kg have been evaluated using lower doses. Current data on delamanid use in these patients are provided in sections "Pharmacological Properties" and "Adverse Reactions"; however, these data are insufficient to support recommendations for use of DELTYBA® 50 mg film-coated tablets in this population.

Overdose

No cases of overdose were observed during clinical trials. However, additional clinical data indicate that the overall safety profile of delamanid in patients receiving 200 mg twice daily (i.e., total daily dose of 400 mg) is similar to that in patients receiving the recommended dose of 100 mg twice daily. Some adverse reactions occurred at higher frequencies, and the incidence of QT interval prolongation increased with increasing dose. In case of overdose, immediate removal of delamanid from the gastrointestinal tract should be performed, along with supportive therapy. Frequent ECG monitoring is required.

Side effects

The most common (> 10%) adverse drug reactions in patients receiving optimized background regimen in combination with delamanid were: nausea (32.9%), vomiting (29.9%), headache (28.4%), sleep disorders and disturbances (28.2%), dizziness (22.4%), gastritis (15.9%), and decreased appetite (13.1%).

Tabulated list of adverse reactions

The list of adverse reactions and their frequency of occurrence are presented in Table 2, based on data obtained from two double-blind, placebo-controlled clinical trials and spontaneous reporting.

Adverse drug reactions are classified by system organ classes using MedDRA terminology. Within each organ system class, adverse reactions are listed in descending order of frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and frequency not known. Within each frequency category, adverse reactions are presented in order of decreasing severity.

Table 2

Adverse reactions observed during administration of delamanid

The above table lists descriptions of adverse reactions using general terms that are primarily used to describe identical or similar medical conditions and events, which have been grouped and presented in Table 2 as a single adverse reaction. The listed adverse reactions were recorded during double-blind clinical trials and include the relevant adverse drug reactions listed below in parentheses.

1 Hypothyroidism (hypothyroidism, primary hypothyroidism).

2 Sleep disorders and disturbances (difficulty falling asleep, insomnia, sleep disturbance, nightmares).

3 Psychotic disorder (acute psychosis, psychotic disorder, reactive psychosis, substance-induced psychotic disorder).

4 Anxiety (anxiety, anxiety disorder, generalized anxiety disorder).

5 Depression (adjustment disorder with depressed mood, depressed state, depression, major depression, mixed anxiety-depressive disorder, persistent depressive disorder, schizoaffective disorder, depressive type).

6 Hallucinations (hallucinations, auditory hallucinations, visual hallucinations, tactile hallucinations, mixed hallucinations, hypnopompic hallucinations, hypnagogic hallucinations).

7 Headache (head discomfort, headache, migraine, sinus headache, tension headache, vascular headache).

8 Gastritis (chronic gastritis, gastritis, erosive gastritis).

9 Increased blood cortisol level (Cushing's syndrome, hyperadrenocorticism, increased blood cortisol level).

Description of selected adverse reactions

Prolongation of QT interval on ECG

In patients who received 200 mg of delamanid daily during Phase 2 and 3 clinical trials, the mean placebo-corrected QTcF interval prolongation compared to baseline ranged from 4.7 ms to 7.6 ms at 1 month and 5.3–12.1 ms at 2 months. The incidence of QTcF interval prolongation > 500 ms ranged from 0.6% (1 of 161) to 2.1% (7 of 341) in patients receiving 200 mg of delamanid daily, compared to 0% (0 of 160) to 1.2% (2 of 170) in patients receiving OBR and placebo. The incidence of QTcF change from baseline > 60 ms ranged from 3.1% (5 of 161) to 10.3% (35 of 341) in patients receiving 200 mg of delamanid daily, compared to 0% (0 of 160) to 7.1% (12 of 170) in patients receiving placebo.

Palpitations

In patients receiving delamanid + OBR during Phase 2 and 3 trials, the frequency of this event was 7.9% (frequency category – "common"), compared to 6.7% in patients receiving placebo + OBR twice daily.

Paediatric patients

Based on data from a study (see section "Pharmacodynamics") involving 37 children aged 0 to 17 years inclusive, the frequency, type, and severity of adverse reactions with delamanid are expected to be similar to those in patients aged 18 years and older. During the post-marketing period, cases of hallucinations have been reported, occurring predominantly in children. The incidence of hallucinations during clinical trials was common in children (5.4%) and adults (1%).

During the post-marketing period, cases of nightmares have been reported, occurring predominantly in children.

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions. Store in the original packaging to protect from moisture at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 48 tablets per pack. Blister packs containing 8 tablets. 6 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Manufacturer of the finished medicinal product: Otsuka Pharmaceutical Co., Ltd.

Batch release responsible manufacturer: R-Pharm Germany GmbH.

Address of manufacturer and location of manufacturing site.

Manufacturer of the finished medicinal product: 13 Minami, Shishitoki, Matsutani, Itano-cho, Itano-gun, Tokushima, 779-0195, Japan.

Batch release responsible manufacturer: Heinrich-Mack-Str. 35, Illertissen, Bayern, 89257, Germany.

Marketing authorization holder.

R-Pharm Germany GmbH.

For drug safety inquiries, contact the 24-hour telephone number +38 050 383 4905 or email [email protected]

Address of marketing authorization holder.

Heinrich-Mack-Str. 35, Illertissen, Bayern, 89257, Germany.