Deltyba (Delamanid): Uses, Dosage & Side Effects

What Is Deltyba and What Is It Used For?

Deltyba contains the active substance delamanid, a nitroimidazo-oxazole derivative that represents a novel class of anti-tuberculosis agents. It was developed by Otsuka Pharmaceutical and received conditional marketing authorization from the European Medicines Agency (EMA) in 2014, making it one of only a few new drugs approved for tuberculosis treatment in over 40 years. Delamanid is also known by its research designation OPC-67683.

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis and primarily affects the lungs, although it can spread to other organs. Multidrug-resistant tuberculosis (MDR-TB) is a form of TB in which the bacteria are resistant to at least isoniazid and rifampicin, the two most potent first-line anti-TB drugs. MDR-TB is substantially more difficult to treat than drug-susceptible TB, requiring longer treatment durations and the use of second-line drugs that are often less effective and more toxic.

Delamanid exerts its anti-tuberculosis effect by inhibiting the synthesis of methoxymycolic acid and ketomycolic acid, which are essential components of the M. tuberculosis cell wall. Mycolic acids are long-chain fatty acids unique to mycobacteria that form a waxy, hydrophobic barrier critical for bacterial survival, virulence, and resistance to host immune defenses. By disrupting this protective cell wall, delamanid causes bacterial cell death. Importantly, delamanid has bactericidal activity against both intracellular (residing within macrophages) and extracellular M. tuberculosis organisms, including dormant bacilli.

The World Health Organization (WHO) includes delamanid in its updated guidelines for the treatment of drug-resistant TB. In the 2022 WHO consolidated guidelines, delamanid is classified as a Group C agent, meaning it can be included in longer MDR/RR-TB treatment regimens when drugs from Groups A and B cannot be used. The WHO recommends delamanid when an effective treatment regimen cannot otherwise be composed from the preferred agents (bedaquiline, linezolid, levofloxacin/moxifloxacin, clofazimine, and cycloserine/terizidone).

Delamanid is specifically indicated for use in adults and children aged 3 years and older, weighing at least 10 kg. It is not intended for use as a monotherapy and must always be administered as part of a multi-drug regimen supervised by a physician experienced in treating drug-resistant tuberculosis. The standard treatment duration with delamanid is 24 weeks (6 months), as part of a longer overall MDR-TB treatment regimen that typically lasts 9 to 20 months depending on the protocol and patient response.

What Should You Know Before Taking Deltyba?

Contraindications

Deltyba should not be used if you have a known hypersensitivity to delamanid or any of the excipients in the formulation. Additionally, delamanid is contraindicated in the following clinical situations:

• Serum albumin below 2.8 g/dL: Low albumin levels are associated with an increased risk of QTc prolongation. Patients must have their serum albumin checked before starting treatment and at regular intervals during therapy.
• Concurrent use with strong CYP3A4 inducers: Drugs such as rifampicin, carbamazepine, and phenytoin significantly reduce delamanid plasma levels and may compromise efficacy.

Warnings and Precautions

Several factors can increase the risk of QTc prolongation during delamanid treatment. Hypoalbuminaemia (low serum albumin) is a significant risk factor because delamanid is highly protein-bound, and lower albumin levels lead to higher free drug concentrations. Electrolyte disturbances, particularly hypokalaemia (low potassium), hypomagnesaemia (low magnesium), and hypocalcaemia (low calcium), must be corrected before and monitored during treatment.

Hepatotoxicity is another important concern. Delamanid can cause elevations in hepatic transaminases (ALT and AST). Liver function tests should be performed before starting treatment and monitored monthly. If transaminase levels rise to more than three times the upper limit of normal accompanied by symptoms, or five times the upper limit of normal regardless of symptoms, delamanid should be discontinued and not restarted.

Patients with severe hepatic impairment (Child-Pugh Class C) should not receive delamanid due to the lack of clinical data in this population. Caution is advised in patients with mild to moderate hepatic impairment, and dose adjustment may be necessary based on clinical response and tolerability.

Pregnancy and Breastfeeding

There are no adequate and well-controlled studies of delamanid in pregnant women. Animal studies have shown some evidence of reproductive toxicity, including effects on embryo-fetal development. Deltyba should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus, which may be the case in life-threatening MDR-TB where no alternative treatments are available.

It is not known whether delamanid or its metabolites are excreted in human breast milk. Because of the potential for adverse effects in nursing infants, a decision must be made whether to discontinue breastfeeding or to discontinue delamanid treatment, taking into account the importance of treatment to the mother and the severity of her disease.

Women of childbearing potential should use effective contraception during treatment with delamanid and for at least 6 months after the last dose. Male patients should also use appropriate contraception during treatment and for at least 3 months after the final dose, as the effects of delamanid on male fertility are not fully characterized.

How Does Deltyba Interact with Other Drugs?

Understanding delamanid's drug interactions is essential because MDR-TB treatment always involves multiple concurrent medications. Delamanid has a unique metabolic pathway: unlike most drugs, it is primarily metabolized by plasma albumin rather than cytochrome P450 (CYP) enzymes. Its main metabolite, DM-6705, is formed through non-enzymatic hydrolysis. However, CYP3A4 plays a minor role in delamanid metabolism, which has clinical implications.

Major Interactions

Minor Interactions and Pharmacokinetic Considerations

Delamanid does not significantly inhibit or induce major CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4) at therapeutic concentrations. Clinical pharmacokinetic studies have demonstrated no clinically significant interactions with the following commonly used anti-TB drugs when administered alongside delamanid:

• Ethambutol: No dose adjustment needed. No significant pharmacokinetic interaction observed.
• Pyrazinamide: No dose adjustment needed. Minimal effect on delamanid exposure.
• Levofloxacin: No dose adjustment needed. Preferred over moxifloxacin due to lower QTc prolongation risk.
• Linezolid: No significant pharmacokinetic interaction. Both drugs can be used in the same regimen with standard monitoring.
• Cycloserine/Terizidone: No pharmacokinetic interaction expected based on differing metabolic pathways.

Regarding antiretroviral drugs for patients with HIV/TB co-infection, efavirenz (a moderate CYP3A4 inducer) reduced delamanid exposure by approximately 25% in pharmacokinetic studies. While this reduction is less pronounced than with rifampicin, clinicians should be aware of potentially sub-therapeutic delamanid levels. Lopinavir/ritonavir (a strong CYP3A4 inhibitor) increased delamanid exposure by approximately 25%, but this increase is not considered clinically significant. No dose adjustments are currently recommended for either antiretroviral combination, but patients should be monitored closely for both efficacy and adverse effects.

Delamanid may have a minor inhibitory effect on P-glycoprotein (P-gp) at the intestinal level. Patients receiving drugs that are P-gp substrates with narrow therapeutic windows (such as digoxin) should be monitored for increased drug levels and potential toxicity.

What Is the Correct Dosage of Deltyba?

Adults

The dosage of delamanid was established through phase IIb clinical trials published in the New England Journal of Medicine (Gler et al., 2012). In this landmark trial, the addition of delamanid 100 mg twice daily to an optimized background regimen significantly increased sputum culture conversion at 2 months compared to placebo (45.4% vs 29.6%, p=0.008). This dose demonstrated the most favorable balance between efficacy and safety, particularly regarding QTc prolongation.

Children (3 Years and Older)

Delamanid has been approved for use in children aged 3 years and older weighing at least 10 kg. Pediatric dosing is based on body weight and uses dispersible tablets (25 mg) for younger children who cannot swallow film-coated tablets:

Pediatric dosing recommendations are based on population pharmacokinetic modeling and limited clinical data from the Phase I pediatric trial (Trial 242-12-232). ECG monitoring in pediatric patients follows the same principles as in adults, with QTcF assessments performed at baseline and at least monthly during treatment.

Elderly Patients

There are limited clinical data on the use of delamanid in patients aged 65 years and older. The pharmacokinetics of delamanid have not been specifically studied in elderly populations. General principles of prescribing in older adults apply: careful monitoring of cardiac, hepatic, and renal function is recommended, and the potential for polypharmacy-related drug interactions should be thoroughly assessed before initiating therapy.

No specific dose adjustment is recommended based on age alone. However, older adults may be more susceptible to QTc prolongation due to age-related changes in cardiac physiology, decreased hepatic function, and the higher likelihood of concomitant medications that affect cardiac repolarization. More frequent ECG monitoring may be warranted in this population.

Missed Dose

If a dose of Deltyba is missed, the patient should take it as soon as they remember, provided it is taken with food. However, if it is nearly time for the next scheduled dose, the missed dose should be skipped entirely. Patients should never take a double dose to make up for a missed one. Consistent adherence to the dosing schedule is essential for maintaining therapeutic drug levels and maximizing treatment efficacy against MDR-TB.

Patients and their caregivers should be educated about the critical importance of treatment adherence in MDR-TB. Missed doses can contribute to the development of further drug resistance and treatment failure. Directly observed therapy (DOT) is strongly recommended by the WHO for all patients receiving MDR-TB treatment, including those taking delamanid.

Overdose

There is limited clinical experience with delamanid overdose. In the event of an overdose, the primary concern is QTc prolongation and the associated risk of cardiac arrhythmias. Management should include:

• Immediate continuous ECG monitoring for at least 24 hours or until the QTc interval normalizes
• Correction of any electrolyte abnormalities (potassium, magnesium, calcium)
• Gastric lavage may be considered if performed within 1-2 hours of ingestion
• Activated charcoal may be given if the patient presents early
• No specific antidote exists; treatment is supportive and symptomatic
• Haemodialysis is unlikely to significantly remove delamanid due to its high protein binding (>99.5%)

What Are the Side Effects of Deltyba?

Like all medicines, Deltyba can cause side effects, although not everybody experiences them. The safety profile of delamanid has been characterized through clinical trials and post-marketing surveillance. The following adverse effects have been reported, classified by frequency according to the MedDRA convention:

It is important to note that many adverse effects reported during delamanid clinical trials may also be attributable to the underlying tuberculosis disease, concomitant anti-TB medications, or the overall poor health status of patients with MDR-TB. Distinguishing drug-related adverse events from disease-related symptoms can be challenging in clinical practice.

The QTc prolongation associated with delamanid is dose-dependent and generally reversible after discontinuation of the drug. In the pivotal clinical trial (Trial 204), the mean QTcF increase from baseline at 2 months was approximately 12.1 milliseconds in the delamanid 100 mg twice daily group compared to 3.8 milliseconds in the placebo group. Monitoring of the DM-6705 metabolite is also relevant, as this metabolite has a very long half-life (121-425 hours) and contributes to QTc prolongation even after delamanid is discontinued.

How Should You Store Deltyba?

Proper storage of Deltyba is important to maintain the drug's stability and therapeutic effectiveness. The following storage conditions should be observed:

• Temperature: Store below 30°C (86°F). Do not freeze.
• Moisture protection: Store in the original blister packaging to protect from moisture. Do not remove tablets from the blister until immediately before use.
• Light protection: No special light protection requirements, but keep in original packaging.
• Child safety: Keep out of the sight and reach of children.
• Expiry date: Do not use after the expiry date stated on the blister and carton after "EXP." The expiry date refers to the last day of that month.

Do not dispose of Deltyba via household waste or wastewater. Anti-tuberculosis drugs require proper disposal to prevent environmental contamination and potential contribution to antimicrobial resistance. Return any unused or expired medication to your pharmacist for safe disposal in accordance with local environmental regulations.

If tablets appear damaged, discolored, or show any signs of deterioration, do not use them and consult your pharmacist for a replacement. Film-coated tablets that have been removed from the blister but not taken should be discarded and not returned to the packaging.

What Does Deltyba Contain?

Understanding the complete composition of Deltyba is important for identifying potential allergies to excipients and for pharmaceutical care:

Active Substance

Each film-coated tablet contains 50 mg of delamanid. Delamanid has the molecular formula C₂₅H₂₅F₃N₄O₆ and a molecular weight of 534.48 g/mol. It is a white to yellow crystalline powder that is practically insoluble in water.

Inactive Ingredients (Excipients)

The tablet core contains the following excipients:

• Hypromellose phthalate (coating agent)
• Povidone (binder)
• All-rac-alpha-tocopherol (antioxidant)
• Stearic acid (lubricant)

The film coating contains:

• Hypromellose (film-forming agent)
• Macrogol (plasticizer)
• Titanium dioxide (E171, white colorant)
• Talc (anti-adherent)
• Iron oxide yellow (E172, colorant)

Tablet Appearance

Deltyba 50 mg film-coated tablets are round, yellow, biconvex tablets debossed with the Otsuka logo and "DLM" on one side. Each tablet is approximately 10.5 mm in diameter. The tablets are supplied in aluminium blister packs containing 48 tablets per carton (4 blisters of 12 tablets each).