Daprotab6 mg

Daprotab is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients who have been receiving dialysis for at least four months. This is the only FDA-approved (established) indication for Daprotab.

• Established/approved use: Anemia of CKD in adult dialysis-dependent patients (hemodialysis or peritoneal dialysis), as an alternative to injectable erythropoiesis-stimulating agents (ESAs).
• Not approved / insufficient evidence: Daprotab is not indicated for anemia in non-dialysis-dependent CKD patients; safety in this population has not been established and adverse events were more frequent in trials of non-dialysis patients.
• Not indicated as a substitute for emergency red blood cell transfusion.

Daprotab should only be used to raise hemoglobin to the minimum level needed to avoid the need for red blood cell transfusion, under the supervision of a physician experienced in managing renal anemia.

Each film-coated tablet contains Daprodustat as the active pharmaceutical ingredient. Daprodustat tablets are available in multiple strengths (e.g., 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, and 24 mg) to allow individualized, hemoglobin-based dose titration. Inactive ingredients are standard tablet excipients (fillers, binders, and film coating) and vary by manufacturer.

Daprotab is an orally administered small-molecule medicine belonging to the class of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). It represents a newer, non-injectable approach to managing anemia associated with chronic kidney disease, offering an oral alternative to injectable erythropoiesis-stimulating agents (ESAs) such as epoetin alfa or darbepoetin alfa in patients who are on chronic dialysis.

Daprotab works by stabilizing hypoxia-inducible factor (HIF), which in turn stimulates the body's own production of erythropoietin (EPO) and improves iron availability, leading to increased red blood cell production.

Mechanism of action: Daprodustat reversibly inhibits prolyl hydroxylase enzymes that normally mark hypoxia-inducible factor (HIF)-alpha subunits for degradation under normal oxygen conditions. By inhibiting these enzymes, Daprodustat allows HIF-alpha to accumulate and activate HIF-dependent gene transcription, mimicking a hypoxic response. This leads to increased endogenous production of erythropoietin, enhanced iron absorption and mobilization, and ultimately increased red blood cell production, without directly injecting exogenous erythropoietin.

Pharmacokinetics: Daprodustat is rapidly absorbed after oral administration, with peak plasma concentrations reached within a few hours. It is highly protein-bound and is primarily metabolized by the hepatic enzyme CYP2C8, with a smaller contribution from UGT1A3. It has a relatively short elimination half-life (roughly 5-13 hours), which supports once-daily oral dosing. Because CYP2C8 is the principal metabolic pathway, exposure to Daprodustat is significantly affected by strong CYP2C8 inhibitors or inducers.

Daprotab is taken by mouth once daily, with or without food, at approximately the same time each day. Tablets should be swallowed whole. Patients on concomitant oral phosphate binders should be advised that these may reduce Daprotab absorption (see Interactions) and appropriate dose timing should be discussed with a physician.

The following are clinically significant, well-documented interactions with Daprotab:

• Strong CYP2C8 inhibitors (e.g., gemfibrozil): Markedly increase Daprotab plasma exposure, raising the risk of adverse effects. Concomitant use is contraindicated.
• Strong CYP2C8 inducers (e.g., rifampin): Substantially decrease Daprotab plasma exposure, which may reduce efficacy; avoid concomitant use if possible, or adjust Daprotab dose and monitor hemoglobin response closely.
• Oral phosphate binders (e.g., sevelamer carbonate, calcium acetate): May reduce absorption and exposure of Daprotab when taken together; separating administration times may be considered, and hemoglobin should be monitored.
• OATP1B1 inhibitors: May increase Daprotab exposure; use with caution.

Patients should inform their physician of all prescription and over-the-counter medicines, herbal products, and supplements they are taking before starting Daprotab.

The most common adverse reactions associated with Daprotab (occurring in ≥10% of patients in clinical trials) include:

• Hypertension (worsening or new-onset)
• Thrombotic vascular events (including vascular access thrombosis)
• Abdominal pain

Other reported adverse effects include diarrhea, nausea, and peritonitis (in peritoneal dialysis patients). Serious but less common effects include gastrointestinal erosions/bleeding, and elevated liver enzymes. See Precautions and Warnings for the boxed warning regarding thrombotic and cardiovascular risk.

Pregnancy: Data on the use of Daprotab in pregnant women are limited. Animal studies have shown embryofetal harm (including fetal loss and reduced fetal weight) at maternally toxic doses. Daprotab should be used during pregnancy only if clearly needed and the potential benefit justifies the potential risk to the fetus; consult a physician before use.

Lactation: There is no data on the presence of Daprotab in human milk or its effects on the breastfed infant or on milk production. Because many drugs are excreted in human milk, a decision should be made whether to discontinue breastfeeding or discontinue Daprotab, taking into account the benefits of breastfeeding and the mother's clinical need for treatment; consult a physician.

Boxed Warning: Thrombotic and Cardiovascular Risk

Daprotab carries a boxed warning for an increased risk of death, myocardial infarction, stroke, venous thromboembolism, and vascular access thrombosis, similar to concerns seen with injectable erythropoiesis-stimulating agents. Use the lowest dose sufficient to reduce the need for transfusion.

Other Precautions

• Hemoglobin overcorrection: Avoid targeting hemoglobin above 11 g/dL; excessive correction is associated with increased cardiovascular risk. Monitor hemoglobin regularly and adjust dose as needed (see Dosage and Administration).
• Hypertension: Daprotab may cause or worsen hypertension; monitor blood pressure regularly and manage appropriately. Contraindicated in uncontrolled hypertension (see Contraindications).
• Gastrointestinal erosion/bleeding: Monitor for signs of GI bleeding, particularly in patients with risk factors.
• Hepatic effects: Periodic monitoring of liver function is reasonable, as elevated liver enzymes have been reported; use with caution in hepatic impairment.
• Malignancy: Because HIF-PHIs may theoretically promote tumor growth via angiogenic pathways, use in patients with active malignancy is not recommended unless benefits outweigh risks.
• Non-dialysis CKD: Daprotab has not been shown to be safe and effective in non-dialysis-dependent CKD patients and is not indicated for this population (see Indications).

There is limited clinical experience with Daprotab overdose. Excessive dosing may be expected to increase the risk of hemoglobin overcorrection and associated thrombotic/cardiovascular events, as well as hypertension. There is no specific antidote for Daprotab overdose.

In case of suspected overdose, seek immediate medical attention or contact a poison control center. Management should include withholding the dose, close monitoring of hemoglobin, blood pressure, and clinical status, and supportive care as directed by a physician.

Store at room temperature (below 30°C), away from light and moisture. Keep out of reach of children.

Renal Impairment

Daprotab is indicated specifically for anemia of CKD in patients on dialysis; it is not recommended for non-dialysis-dependent CKD patients due to lack of established safety and efficacy (see Indications).

Hepatic Impairment

Use with caution in patients with hepatic impairment; Daprotab is primarily metabolized by the liver and periodic liver function monitoring is reasonable. Use in severe hepatic impairment has not been well studied and is generally not recommended.

Elderly

No overall differences in safety or effectiveness have been reported between elderly and younger adult patients, but elderly patients may have a higher baseline risk of cardiovascular events; monitor closely.

Pediatric Use

Safety and efficacy of Daprotab in pediatric patients have not been established (see Pediatric Uses).

Daprotab is generally used long-term as chronic maintenance therapy for anemia of CKD in dialysis-dependent patients, for as long as the patient remains on dialysis and continues to require pharmacologic management of anemia. The dose and continued need for therapy should be reassessed periodically by the treating physician based on hemoglobin levels, iron status, and overall clinical response.

Anti-anemic agent; Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI)

Daprodustat inhibits prolyl hydroxylase enzymes, stabilizing hypoxia-inducible factor (HIF) and thereby stimulating the body's own erythropoietin production and improving iron availability to increase red blood cell formation.

The safety and efficacy of Daprotab have not been established in pediatric patients. Daprotab is not currently approved or recommended for use in children or adolescents. Anemia of CKD in pediatric patients should be managed according to pediatric nephrology guidelines using therapies with established safety data in this age group.