Deltyba Special Precautions

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 CYP3A4 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 considered 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), bedaquiline, triazole antifungal agents, pentamidine, saquinavir; certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine); certain antimalarials with QT-prolonging potential (e.g. halofantrine, quinine, chloroquine, artesunate/amodiaquine, dihydroartemisinin/piperaquine); 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 CYP3A4: Co-administration of delamanid with a strong inhibitor of CYP3A4 (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 CYP3A4 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 Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Renal impairment: There are no data on the use of delamanid in patients with severe renal impairment and its use is not recommended (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Paradoxical drug reaction: Post-marketing cases of paradoxical drug reactions (clinical or radiological worsening of existing lesions or development of new lesions in a patient who had previously shown improvement with appropriate antimycobacterial treatment) have been reported with Deltyba. Paradoxical drug reactions are often transient and should not be misinterpreted as failure to respond to treatment. If a paradoxical response is suspected, continuation of planned combination therapy is recommended and symptomatic therapy to suppress the exaggerated immune reaction should be initiated if necessary (see Adverse Reactions).
Excipients: Deltyba film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effects on ability to drive and use machines: Deltyba is expected to have a moderate influence on the ability to drive and use machines. 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 is very common and tremor is common).