Diaquinolin (Tablets) Instructions for Use

Marketing Authorization Holder

Jodas Expoim, LLC (Russia)

Manufactured By

Oxford Laboratories, Pvt. Ltd. (India)

Or

Interpharma, LLC (Russia)

ATC Code

J04AK05 (Bedaquiline)

Active Substance

Bedaquiline (Rec.INN registered by WHO)

Dosage Form

Diaquinolin

Tablets 100 mg

Dosage Form, Packaging, and Composition

Tablets

10 pcs. – blister packs – cardboard packs (10 pcs.) – By prescription
188 pcs. – jars – cardboard packs (188 pcs.) – By prescription
188 pcs. – bottles – cardboard packs (188 pcs.) – By prescription

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Agents active against mycobacteria; antituberculosis agents; other antituberculosis agents

Pharmacological Action

Bedaquiline belongs to the diarylquinoline group – a new class of antituberculosis compounds.

The bactericidal action of the drug is due to the specific inhibition of the mycobacterial ATP synthase proton pump (adenosine 5’triphosphate synthase) – an enzyme that plays a major role in the process of cellular respiration of Mycobacterium tuberculosis.

Inhibition of ATP synthesis leads to disruption of energy production and, as a result, to the death of the microbial cell (dividing and dormant microorganisms).

Pharmacokinetics

High absorption of bedaquiline was noted after oral administration.

C_max in plasma is reached approximately 5 hours after administration.

C_max and AUC increase proportionally with increasing dose up to the highest doses studied (700 mg/day as a single dose and 400 mg in divided doses).

The highest bioavailability is achieved when taken with food, which is approximately 2 times higher than bioavailability when taken on an empty stomach.

Plasma protein binding is > 99.9% for all species studied, including humans.

Plasma protein binding of the N-monodesmethyl metabolite (M2) in humans is at least 99.8%.

In animals, Bedaquiline and its active metabolite N-monodesmethyl (M2) were actively distributed in most tissues, but penetration through the BBB is insignificant.

The main isoenzyme involved in the metabolism of bedaquiline and the formation of M2 in vitro is CYP3A4.

Bedaquiline, unlike M2, was a weak substrate of OCT1, OATP1B1 and OATP1B3 in in vitro studies.

An in vitro study showed that Bedaquiline, at concentrations achieved in the intestine after oral administration, may inhibit BCRP.

The clinical significance has not been established.

Bedaquiline is eliminated from the body mainly through the intestine.

In clinical studies, the excretion of unchanged bedaquiline by the kidneys was ≤ 0.001% of the administered dose, indicating insignificant renal clearance of the unchanged substance.

After reaching C_max, bedaquiline in plasma decreases in a triexponential manner.

The terminal T_1/2 of bedaquiline and M2 is about 5 months (on average from 2 to 8 months), which probably reflects the slow release of bedaquiline and M2 from peripheral tissues.

Indications

Adults and adolescents from 12 to 18 years of age weighing at least 30 kg – as part of combination therapy for pulmonary tuberculosis caused by strains of Mycobacterium tuberculosis with multidrug resistance.

It is used when another effective treatment regimen cannot be prescribed due to pathogen resistance or intolerance to other antibacterial drugs.

Dosage Regimen

Orally.

A single dose is 200-400 mg.

Treatment should be carried out under the direct supervision of a specialist experienced in the treatment of multidrug-resistant tuberculosis (MDR-TB).

Bedaquiline should be used in combination with at least 3 drugs to which the strain of Mycobacterium tuberculosis isolated from the patient has proven in vitro susceptibility.

If in vitro drug susceptibility test results are not available, Bedaquiline should be used in combination with 4 other drugs to which the strain of Mycobacterium tuberculosis isolated from the patient may remain susceptible.

When choosing the regimen and duration of administration of reserve antituberculosis drugs as part of combination therapy, the attending physician should be guided by state standards for the treatment of tuberculosis, data on drug resistance of mycobacteria in the region, taking into account the drug sensitivity of the strain isolated from the tuberculosis patient, and data from clinical and radiological examination.

Adverse Reactions

Nervous system disorders very common – headache, dizziness.

Cardiovascular system disorders common – QT interval prolongation on ECG.

Digestive system disorders very common – nausea, vomiting; common – diarrhea.

Hepatobiliary disorders common – increased transaminase activity.

Musculoskeletal and connective tissue disorders very common – arthralgia; common – myalgia.

Contraindications

Hypersensitivity to bedaquiline; breastfeeding; age under 12 years.

Use in Pregnancy and Lactation

Use during pregnancy is possible only in cases where the potential benefit to the mother outweighs the risk to the fetus.

Bedaquiline is excreted in breast milk. Women receiving Bedaquiline should refrain from breastfeeding.

Use in Hepatic Impairment

Dose adjustment for patients with mild or moderate hepatic impairment is not required. The pharmacokinetics of bedaquiline in patients with severe hepatic insufficiency have not been studied.

Use in Renal Impairment

For patients with mild or moderate renal impairment, dose adjustment is not required.

It is not recommended to use Bedaquiline in patients with severe renal impairment (CrCl < 30 ml/min) or end-stage renal disease requiring hemodialysis or peritoneal dialysis.

Pediatric Use

Should not be used in patients under 12 years of age weighing less than 30 kg.

Geriatric Use

The pharmacokinetics of bedaquiline do not depend on age (age range from 18 to 68 years).

Special Precautions

There are no clinical data on the use of bedaquiline for the treatment of the following diseases: extrapulmonary tuberculosis (e.g., CNS tuberculosis, bone tuberculosis); mycobacterial infections other than those caused by Mycobacterium tuberculosis; latent infection caused by Mycobacterium tuberculosis.

Clinical data on the use of bedaquiline as part of combination therapy for pulmonary tuberculosis caused by Mycobacterium tuberculosis bacteria susceptible to bedaquiline are lacking.

Bedaquiline should be used only in an appropriate combination regimen for the treatment of MDR-TB, as recommended by state standards for the treatment of tuberculosis, to prevent the development of drug resistance.

An ECG (electrocardiogram) must be performed before starting treatment with bedaquiline and then at least once a month after starting treatment.

Before starting therapy, it is necessary to determine the level of potassium, calcium and magnesium in the blood and, if abnormal, correction is necessary.

If the QT interval is prolonged, electrolyte levels should be monitored.

When using bedaquiline concomitantly with drugs that prolong the QT interval (including delamanid and levofloxacin), an additive or synergistic effect cannot be ruled out, which may lead to QT interval prolongation.

Caution should be exercised when using bedaquiline concomitantly with drugs that can cause QT interval prolongation.

In case of concomitant use of such drugs with bedaquiline, clinical monitoring, including regular ECG monitoring, should be carried out.

If concomitant use of clofazimine with bedaquiline is necessary, clinical observation of the patient, including regular ECG monitoring, is recommended.

It is not recommended to start taking bedaquiline in patients with the following conditions, except in cases where the benefit of bedaquiline significantly outweighs the possible risk: heart failure; QT interval corrected using Fridericia’s formula (QTcF) >450 ms (confirmed by repeated ECG study); personal or family history of congenital long QT syndrome or development of torsades de pointes; hypothyroidism, including in history; bradyarrhythmia, including in history; concomitant use with fluoroquinolone antibiotics that cause significant QT interval prolongation (e.g., gatifloxacin, moxifloxacin, sparfloxacin); hypokalemia.

Bedaquiline should be discontinued if the patient develops: clinically significant ventricular arrhythmia; QT interval corrected using Fridericia’s formula (QTcF) >500 ms (confirmed by repeated ECG study).

In case of syncope, an ECG should be performed to determine QT interval prolongation.

Patients should be monitored throughout the course of treatment due to the observed slow increase in liver enzyme levels with a gradual increase over 24 weeks.

It is necessary to monitor the appearance of symptoms and the results of laboratory tests (ALT, AST, ALP and bilirubin) at the beginning of therapy, monthly during treatment and as needed.

If AST and ALT are 5 times the ULN, the treatment regimen should be reviewed, and it is also necessary to discontinue treatment with bedaquiline and/or any background therapy with hepatotoxic drugs.

During treatment with bedaquiline, the use of other hepatotoxic drugs and alcohol should be avoided, especially in patients with impaired liver function.

It is assumed that in adolescents weighing from 30 to 40 kg, the average exposure will be higher compared to adult patients.

This may be associated with an increased risk of QT interval prolongation or hepatotoxicity.

Effect on ability to drive vehicles and operate machinery

If adverse reactions from the central nervous system (e.g., dizziness) occur while using bedaquiline, patients are advised to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration, speed of psychomotor and motor reactions.

Drug Interactions

Exposure to bedaquiline may decrease when used concomitantly with CYP3A4 inducers.

In a drug interaction study of bedaquiline and rifampicin, administered as a single dose, in healthy volunteers, the AUC of bedaquiline decreased by 52% [90% CI (-57; -46)].

Due to the possibility of reducing the therapeutic effect of bedaquiline due to a decrease in its systemic action, concomitant use of the drug with moderate or strong CYP3A4 inducers (for example, efavirenz, etravirine, rifamycins, including rifampicin, rifapentine and rifabutin, carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum)), prescribed systemically, should be avoided.

Exposure to bedaquiline may increase when used concomitantly with CYP3A4 inhibitors.

With short-term concomitant use of ketoconazole and bedaquiline in healthy volunteers, the AUC of bedaquiline increased by 22% [90% CI (12; 32)].

A more pronounced effect of bedaquiline may be observed during long-term concomitant use with ketoconazole or other CYP3A4 inhibitors.

Due to the potential risk of adverse reactions due to increased therapeutic action of bedaquiline, long-term concomitant use (more than 14 days) of bedaquiline with moderate or potent CYP3A4 inhibitors (ciprofloxacin, erythromycin, fluconazole, clarithromycin, ketoconazole, ritonavir), prescribed systemically, should be avoided.

If concomitant use is necessary, more frequent monitoring of ECG and liver transaminase activity is recommended.

Concomitant use of bedaquiline with isoniazid/pyrazinamide in healthy volunteers did not cause clinically significant changes in the AUC of bedaquiline, isoniazid or pyrazinamide.

No dose adjustment is required when bedaquiline is used concomitantly with isoniazid or pyrazinamide.

No significant effect of bedaquiline on the pharmacokinetics of ethambutol, kanamycin, pyrazinamide, ofloxacin or cycloserine was observed when used concomitantly.

With a single dose of bedaquiline and multiple doses of lopinavir/ritonavir, the AUC of bedaquiline increased by 22% [90% CI (11; 34)].

A more pronounced effect on the plasma concentration of bedaquiline may be observed during long-term concomitant use with lopinavir/ritonavir.

In patients receiving bedaquiline treatment as part of treatment for drug-resistant tuberculosis and antiretroviral therapy based on lopinavir/ritonavir, it was shown that over 48 hours the AUC of bedaquiline increases approximately 2 times.

This increase is most likely due to ritonavir.

If the benefit significantly outweighs the risk, Bedaquiline can be used with caution concomitantly with lopinavir/ritonavir.

An increase in the plasma concentration of bedaquiline is expected when used concomitantly with other ritonavir-boosted HIV protease inhibitors.

It should be noted that it is not recommended to adjust the dosage of bedaquiline in cases of combination therapy with lopinavir/ritonavir or other ritonavir-boosted HIV protease inhibitors.

Data supporting a reduced dose of bedaquiline in such cases are lacking.

Concomitant use of a single dose of bedaquiline and multiple doses of nevirapine did not lead to clinically significant changes in the plasma concentration of bedaquiline.

Clinical data on the concomitant use of antiretroviral drugs and bedaquiline in HIV-infected patients with MDR-TB are lacking.

Efavirenz is a moderate inducer of CYP3A4 activity, and its concomitant use with bedaquiline may lead to a decrease in the AUC of bedaquiline and loss of activity, and therefore is not recommended.

An additive or synergistic effect on QT interval prolongation was observed when bedaquiline was used concomitantly with drugs that prolong the QT interval.

In a clinical drug interaction study of ketoconazole and bedaquiline, after repeated concomitant administration of the drugs, a more significant effect on QTc was observed than after repeated administration of each of these drugs separately.

An additive or synergistic effect on QT interval prolongation when bedaquiline is used concomitantly with drugs that prolong the QT interval cannot be ruled out.

Periodic monitoring is recommended.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.