Deltyba Special Precautions

There are no data on treatment with delamanid for more than 24 consecutive weeks.
There are no clinical data on the use of delamanid to treat: Extra pulmonary tuberculosis (e.g. central nervous system, bone); infections due to Mycobacterial species other than those of the M. tuberculosis complex; latent infection with M. tuberculosis.
There are no clinical data on the use of delamanid as part of combination regimens used to treat drug-susceptible M. tuberculosis.
Resistance to delamanid: Delamanid must only be used in an appropriate combination regimen for MDR-TB treatment as recommended by WHO to prevent development of resistance to delamanid.
QT prolongation: QT prolongation has been observed in patients treated with delamanid. This prolongation increases slowly over time in the first 6-10 weeks of treatment and remains stable thereafter. QTc prolongation is very closely correlated with the major delamanid metabolite DM-6705. Plasma albumin and CYP3A regulate the formation and metabolism of DM-6705 respectively (see Special Considerations as follows).
General recommendations: It is recommended that electrocardiograms (ECG) should be obtained before initiation of treatment and monthly during the full course of treatment with delamanid. If a QTcF >500 ms is observed either before the first dose of delamanid or during delamanid treatment, treatment with delamanid should either not be started or should be discontinued. If the QTc interval duration exceeds 450/470 ms for male/female patients during delamanid treatment, these patients should be administered more frequent ECG monitoring. It is also recommended that serum electrolytes, e.g. potassium, are obtained at baseline and corrected if abnormal.
Special Considerations: Cardiac risk factors: Treatment with delamanid should not be initiated in patients with the following risk factors unless the possible benefit of delamanid is considerd to outweigh the potential risks. Such patients should receive very frequent monitoring of ECG throughout the full delamanid treatment period.
Known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval or QTc >500 ms.
History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.
Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failure accompanied by reduced left ventricle ejection fraction.
Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia.
Taking medicinal products that are known to prolong the QTc interval. These include (but are not limited to): Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol); neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine), antidepressive agents; certain antimicrobial agents, including: macrolides (e.g. erythromycin, clarithromycin), moxifloxacin, sparfloxacin (see Precautions regarding use with other fluoroquinolones), triazole antifungal agents, pentamidine, saquinavir; certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine); cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide.
Hypoalbuminaemia: In a clinical study, the presence of hypoalbuminaemia was associated with an increased risk of prolongation of the QTc interval in delamanid treated patients. Delamanid is contraindicated in patients with albumin <2.8 g/dL (see Contraindications). Patients who commence delamanid with serum albumin <3.4 g/dL or experience a fall in serum albumin into this range during treatment should receive very frequent monitoring of ECGs throughout the full delamanid treatment period.
Co-administration with strong inhibitors of CYP3A: Co-administration of delamanid with a strong inhibitor of CYP3A (lopinavir/ritonavir) was associated with a 30% higher exposure to the metabolite DM-6705, which has been associated with QTc prolongation. Therefore if co-administration of delamanid with any strong inhibitor of CYP3A is considered necessary it is recommended that there is very frequent monitoring of ECGs, throughout the full delamanid treatment period.
Co-administration of delamanid with quinolones: All QTcF prolongations above 60 ms were associated with concomitant fluoroquinolone use. Therefore if co-administration is considered to be unavoidable in order to construct an adequate treatment regimen for MDR-TB it is recommended that there is very frequent monitoring of ECGs throughout the full delamanid treatment period.
Hepatic impairment: Deltyba is not recommended in patients with moderate to severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Biotransformation and elimination: The complete metabolic profile of delamanid in man has not yet been fully elucidated (see Pharmacology: Pharmacokinetics under Actions, and Interactions). Therefore the potential for drug-drug interactions of clinical significance to occur with delamanid and the possible consequences, including the total effect on the QTc interval, cannot be predicted with confidence.
Excipients: Deltyba film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Effects on the ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised not to drive or use machines if they experience any adverse reaction with a potential impact on the ability to perform these activities (e.g. headache and tremor are very common).