Kapruvia (Difelikefalin)
Kappa-Opioid Receptor Agonist for CKD-Associated Pruritus in Hemodialysis Patients
Quick Facts About Kapruvia
Key Takeaways About Kapruvia
- First targeted treatment for CKD-associated itch: Kapruvia is the first medicine specifically approved to treat pruritus caused by chronic kidney disease in hemodialysis patients
- Administered during dialysis: Given as an intravenous injection at the end of each hemodialysis session (typically 3 times per week), so no additional hospital visits are needed
- Does not cross the blood-brain barrier: Unlike traditional opioids, difelikefalin acts peripherally, significantly reducing the risk of euphoria, respiratory depression, and addiction
- Improvement takes 2–3 weeks: Patients should expect the anti-itch effect to develop gradually over the first few weeks of treatment
- Most common side effects are mild: Drowsiness and tingling sensations are the most frequently reported adverse effects, and they are generally well-tolerated
What Is Kapruvia and What Is It Used For?
Kapruvia (difelikefalin) is a selective kappa-opioid receptor agonist approved for the treatment of moderate-to-severe pruritus (itching) in adult patients with chronic kidney disease (CKD) who are undergoing hemodialysis. It works by activating kappa-opioid receptors on peripheral nerves and immune cells to reduce the sensation of itch.
Chronic kidney disease-associated pruritus (CKD-aP) is one of the most common and distressing symptoms experienced by patients undergoing hemodialysis. Studies estimate that between 40% and 70% of hemodialysis patients are affected by moderate-to-severe itching, yet for decades this condition has been inadequately treated. CKD-associated pruritus significantly impairs quality of life, disrupts sleep, increases the risk of depression, and has been associated with higher mortality rates in dialysis patients.
Kapruvia contains the active substance difelikefalin, a synthetic D-amino acid peptide that selectively activates kappa-opioid receptors (KORs). These receptors are found on sensory nerve endings and immune cells throughout the body and play a key role in modulating the perception of itch. By stimulating peripheral kappa-opioid receptors, difelikefalin inhibits the itch signalling pathways without producing the euphoric, addictive, or respiratory depressant effects associated with mu-opioid receptor activation.
A critical feature of difelikefalin is that it does not significantly cross the blood-brain barrier (the protective barrier between blood vessels and the brain). This is because of its peptide structure, which limits its ability to penetrate the central nervous system (CNS). As a result, Kapruvia produces its anti-pruritic (anti-itch) effects peripherally, with a markedly lower risk of the CNS side effects typically associated with opioid medications, such as euphoria, sedation, respiratory depression, and physical dependence.
The mechanism underlying CKD-associated pruritus is complex and multifactorial. It involves an imbalance in the opioid receptor system, with overactivation of mu-opioid receptors and underactivation of kappa-opioid receptors. Uraemic toxins, systemic inflammation, xerosis (dry skin), elevated calcium and phosphate levels, and neuropathy all contribute to the itch signal. By selectively stimulating kappa-opioid receptors, difelikefalin helps restore the balance in the opioid system and dampens the peripheral itch signals transmitted to the brain.
Kapruvia was approved by the European Medicines Agency (EMA) in April 2022 and by the U.S. Food and Drug Administration (FDA) in August 2021. It represents a significant advance in the management of CKD-associated pruritus, a condition that had no specifically approved pharmacological treatment before its introduction. The approval was based on two large, randomised, double-blind, placebo-controlled phase III clinical trials (KALM-1 and KALM-2) involving over 800 hemodialysis patients.
What Should You Know Before Using Kapruvia?
Before receiving Kapruvia, inform your doctor about all your medical conditions, particularly any conditions affecting the blood-brain barrier, heart rhythm disorders, or liver disease. Tell your doctor about all other medications you are taking, especially sedatives, antihistamines, and opioid pain relievers.
Contraindications
You should not receive Kapruvia if you are allergic to difelikefalin or any of the other ingredients contained in this medicine. The other ingredients include acetic acid (for pH adjustment), sodium acetate trihydrate (for pH adjustment), sodium chloride, and water for injections.
If you have previously experienced an allergic reaction to difelikefalin, including symptoms such as skin rash, itching (distinct from your CKD-related pruritus), swelling of the face, lips, tongue, or throat, or difficulty breathing, you must inform your healthcare team immediately. In such cases, Kapruvia should not be administered again.
Warnings and Precautions
Talk to your doctor or nurse before receiving Kapruvia if any of the following apply to you:
- Elevated potassium levels (hyperkalaemia): Your doctor should monitor your blood potassium levels, as hyperkalaemia is common in dialysis patients and may require attention before starting treatment
- Heart conditions: If you have or have had heart failure, heart rhythm disturbances (arrhythmias), or other significant cardiac conditions, your doctor should evaluate the risks and benefits of Kapruvia treatment
- Impaired blood-brain barrier: If you have conditions that may compromise the blood-brain barrier, such as brain tumours, central nervous system cancers, multiple sclerosis, Alzheimer's disease, or other forms of dementia, there may be an increased risk of central nervous system side effects because more difelikefalin could enter the brain
- Age 65 years or older: Elderly patients may be more susceptible to drowsiness (somnolence) caused by the medication, and extra caution is warranted
- Severe liver impairment: Kapruvia has not been studied in patients with severe hepatic impairment and is therefore not recommended for this patient group. No dose adjustment is needed for patients with mild or moderate liver impairment
- Use of other sedating medications: If you are taking medicines that may cause drowsiness or dizziness, including sedatives, anxiolytics (anti-anxiety medications), sedating antihistamines (used for allergies, colds, nausea, or vomiting), or opioid pain relievers, the combined effects may increase your risk of somnolence and dizziness
Kapruvia may cause drowsiness (somnolence) and dizziness, which can impair your ability to react. Do not drive, operate heavy machinery, or engage in activities requiring alertness until you know how Kapruvia affects you. This is especially important at the start of treatment or if your dose changes.
Use in Children and Adolescents
Kapruvia is not recommended for use in children and adolescents under 18 years of age. The safety and effectiveness of difelikefalin have not been established in paediatric populations. Clinical trials have been conducted exclusively in adult hemodialysis patients. If a child or adolescent with chronic kidney disease experiences significant pruritus, their nephrologist should be consulted for alternative management strategies.
Pregnancy and Breastfeeding
The safety of Kapruvia during pregnancy has not been established. No clinical studies of difelikefalin have been conducted in pregnant women, and it is not known whether difelikefalin can harm an unborn baby. If you are pregnant, think you may be pregnant, or are planning to become pregnant, you should inform your doctor before receiving Kapruvia. Your doctor will carefully weigh the potential benefits of treatment against any possible risks to the foetus.
It is not known whether difelikefalin passes into breast milk. If you are breastfeeding, your doctor will advise you whether to discontinue breastfeeding or to stop receiving Kapruvia, taking into account the benefit of breastfeeding for the child and the benefit of Kapruvia treatment for you. You and your doctor should make this decision together based on your individual circumstances.
Driving and Operating Machinery
Kapruvia can cause somnolence (drowsiness) and dizziness, which may impair your ability to react safely. You should not drive a car or operate machinery if you experience these symptoms or if you do not yet know how Kapruvia affects your ability to react. This precaution is particularly important during the initial treatment period, as your body adjusts to the medication. If symptoms persist, discuss them with your healthcare provider.
How Does Kapruvia Interact with Other Drugs?
Kapruvia may interact with medications that cause drowsiness or slow brain function, including sedatives, opioid analgesics, and sedating antihistamines. These combinations can increase the risk of somnolence and dizziness. Always inform your doctor about all medications you are using.
While difelikefalin does not have extensive metabolic drug interactions (since it is a peptide that is not significantly metabolised by liver enzymes such as CYP450), pharmacodynamic interactions are clinically relevant. The primary concern is the additive sedating effect when Kapruvia is combined with other central nervous system depressants. Tell your doctor about all medications you are currently taking, have recently taken, or might take in the future.
Clinically Significant Interactions
| Drug / Class | Category | Effect | Recommendation |
|---|---|---|---|
| Opioid analgesics (morphine, oxycodone, fentanyl) | Strong pain relievers | Additive sedation and drowsiness; potential for increased CNS depression | Use with caution; monitor closely for excessive somnolence |
| Benzodiazepines (diazepam, lorazepam, alprazolam) | Sedatives / anxiolytics | Additive CNS depression, increased risk of drowsiness and impaired alertness | Use combination cautiously; consider dose adjustments of sedatives |
| Sedating antihistamines (diphenhydramine, chlorphenamine, promethazine) | Allergy / cold / anti-nausea medications | Enhanced sedation and drowsiness when combined with Kapruvia | Avoid if possible; if necessary, use lowest effective dose |
| Sleep medications (zolpidem, zopiclone, eszopiclone) | Hypnotics | Increased risk of excessive sedation and impaired consciousness | Monitor patient closely; timing of sleep medication may need adjustment |
| Gabapentinoids (gabapentin, pregabalin) | Neuropathic pain / anti-seizure | Potential for additive somnolence and dizziness | Use with caution in combination; commonly co-prescribed in dialysis patients |
Additional Considerations
Because difelikefalin is a peptide and is not significantly metabolised by hepatic CYP450 enzymes, it has a low potential for traditional pharmacokinetic drug interactions. It is not expected to alter the blood levels of most other medications. However, patients undergoing hemodialysis are typically taking multiple medications, and the cumulative sedating effects of combined therapies should always be assessed by the healthcare team.
There is currently no evidence that Kapruvia interacts with common dialysis-related medications such as erythropoiesis-stimulating agents (ESAs), phosphate binders, vitamin D analogues, or iron supplements. However, as with any relatively new medication, patients should continue to report any unusual symptoms to their dialysis team.
Kapruvia contains less than 1 mmol (23 mg) of sodium per vial, meaning it is essentially sodium-free. This is relevant for patients on sodium-restricted diets, which is common in CKD management.
What Is the Correct Dosage of Kapruvia?
Kapruvia is administered as an intravenous injection at the end of hemodialysis. The dose is 0.5 micrograms per kilogram of dry body weight, given three times per week (or four times if a fourth dialysis session is required). It is always given by a healthcare professional.
Your doctor will calculate the correct dose of Kapruvia based on your dry body weight (your target weight after dialysis-related fluid has been removed). The medication is injected into a vein by a doctor or nurse at the end of your hemodialysis treatment, via the venous blood line (the tubing that connects you to the dialysis machine) after the rinse-back procedure.
Adults
| Parameter | Details |
|---|---|
| Standard dose | 0.5 micrograms per kilogram of dry body weight |
| Route | Intravenous injection into the venous line of the dialysis circuit |
| Timing | At the end of each hemodialysis session, after rinse-back |
| Frequency | 3 times per week (increased to 4 times if a 4th dialysis is required) |
| Maximum frequency | No more than 4 doses per week, even if more than 4 dialysis sessions occur |
| Onset of effect | Itch reduction expected after 2–3 weeks of treatment |
The dose is weight-based, and your healthcare team will adjust it if your dry body weight changes significantly. The vial contains 50 micrograms of difelikefalin per 1.0 mL of solution, and the appropriate volume is drawn up and injected by your nurse or doctor. For example, a patient weighing 70 kg would receive 35 micrograms (0.7 mL of the solution) per dialysis session.
Elderly Patients
No dose adjustment is generally required for elderly patients based solely on age. However, patients aged 65 years and older may be more susceptible to the sedative effects of Kapruvia, including drowsiness and dizziness. Healthcare providers should monitor elderly patients more closely, especially during the initial treatment period, and consider the overall medication burden that may contribute to additive sedation.
Patients with Liver Impairment
No dose adjustment is necessary for patients with mild or moderate hepatic impairment. However, Kapruvia is not recommended for patients with severe hepatic impairment because it has not been studied in this population. If you have liver disease, inform your doctor so they can determine whether Kapruvia is appropriate for you.
Children
Kapruvia has not been studied in children and adolescents under 18 years of age. It is therefore not recommended for use in paediatric patients. There are currently no established dosage guidelines for this age group.
Missed Dose
If a hemodialysis session is not completed, your doctor will decide whether it is better for you to receive Kapruvia after that incomplete session or to wait until the next scheduled dialysis treatment. If an entire dialysis session is missed, the usual dose of Kapruvia will simply be given at the next dialysis session. There is no need to take a double dose to make up for a missed one.
Overdose
Since Kapruvia is administered by healthcare professionals in a controlled clinical setting, the risk of overdose is very low. However, if an overdose occurs, it may increase the frequency and severity of known side effects, particularly drowsiness, dizziness, and changes in mental status. If you suspect that you have received too much Kapruvia, inform your doctor or nurse immediately. Treatment is supportive, as there is no specific antidote. Your healthcare team will monitor your symptoms and provide appropriate care.
What Are the Side Effects of Kapruvia?
Like all medicines, Kapruvia can cause side effects, although not everyone experiences them. The most common side effects are somnolence (drowsiness) and paraesthesia (tingling, prickling, or numbness of the skin). Most side effects are mild to moderate and tend to be well-tolerated.
The side effects listed below were observed during clinical trials and post-marketing experience with Kapruvia. They are classified by how frequently they occur. If you experience any side effects, including any not listed below, talk to your doctor or nurse. It is important to report any suspected adverse effects to help ongoing safety monitoring of this relatively new medication.
Common
- Somnolence (drowsiness, sleepiness) – the most frequently reported side effect; tends to be mild and may diminish with continued treatment
- Paraesthesia (abnormal skin sensations such as tingling, prickling, burning sensation, numbness, or decreased sensitivity) – usually temporary and not severe
Uncommon
- Dizziness – a sensation of unsteadiness or light-headedness
- Headache – mild to moderate in intensity
- Mental status changes – alterations in alertness and clarity of thought, including confusion; more likely in elderly patients or those taking other sedating medications
- Nausea – a feeling of sickness in the stomach
- Vomiting – usually mild and transient
- Diarrhoea – loose or watery stools
Most of the side effects reported with Kapruvia are neurological in nature and relate to the drug's activity on the opioid receptor system. Because difelikefalin does not significantly cross the blood-brain barrier in patients with an intact barrier, central side effects are relatively infrequent. However, in patients with a compromised blood-brain barrier (for instance, due to brain tumours, multiple sclerosis, or advanced dementia), there may be an increased risk of CNS-related adverse effects.
In the pivotal KALM-1 and KALM-2 clinical trials, the overall safety profile of Kapruvia was favourable compared to placebo. The discontinuation rate due to adverse events was low, and serious adverse events directly attributable to difelikefalin were rare. The somnolence observed tended to occur shortly after injection and was generally transient.
It is important to report any suspected side effects after a medicine has been authorised. This allows continuous monitoring of the benefit-risk balance. Healthcare professionals and patients can report suspected adverse reactions to their national regulatory authority (e.g., the EMA in Europe, the FDA in the United States, or the MHRA in the United Kingdom).
How Should You Store Kapruvia?
Kapruvia should be stored out of the sight and reach of children and should not be used after the expiry date printed on the label and carton. No special storage conditions are required.
Since Kapruvia is administered by healthcare professionals in a dialysis setting, patients do not typically need to store this medication themselves. However, it is useful to know the storage requirements:
- Keep out of the sight and reach of children
- Do not use after the expiry date (marked “EXP” on the label and carton). The expiry date refers to the last day of the stated month
- No special storage conditions are required – store at room temperature; no refrigeration is needed
- The solution should be inspected visually before use. Kapruvia is a clear, colourless solution free from visible particles. Do not use the medicine if it appears cloudy, discoloured, or contains particles
- Each vial is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements
What Does Kapruvia Contain?
Each vial of Kapruvia contains 50 micrograms of difelikefalin (as acetate) in 1.0 mL of solution. The other ingredients are acetic acid, sodium acetate trihydrate, sodium chloride, and water for injections.
Active Ingredient
The active substance is difelikefalin. Each glass vial contains 50 micrograms of difelikefalin (as the acetate salt) in 1.0 mL of solution, giving a concentration of 50 micrograms per millilitre.
Inactive Ingredients (Excipients)
- Acetic acid – used for pH adjustment to ensure the solution has the correct acidity for injection
- Sodium acetate trihydrate – used as a buffer for pH adjustment
- Sodium chloride – provides isotonicity to make the solution compatible with the body's fluids
- Water for injections – the solvent used to dissolve the active ingredient and other components
Appearance and Pack Sizes
Kapruvia is a clear, colourless solution free from particles, with a pH of 4.5. It is supplied in a glass vial sealed with a rubber stopper, an aluminium seal, and a blue plastic flip-off cap. The medicine is available in pack sizes of 3 vials and 12 vials. Not all pack sizes may be marketed in every country.
Marketing Authorisation Holder
Kapruvia is manufactured by Vifor Fresenius Medical Care Renal Pharma France (now part of CSL Vifor), based in Paris La Défense, France. For further information about this medicine, contact the marketing authorisation holder or consult the European Medicines Agency (EMA) website.
How Does Kapruvia Work? Mechanism of Action
Kapruvia works by selectively activating kappa-opioid receptors (KORs) on peripheral nerve endings and immune cells. This action modulates itch signalling pathways and reduces the perception of pruritus without significantly entering the brain, thus avoiding the central side effects typical of opioid medications.
The human body has three main types of opioid receptors: mu (μ), delta (δ), and kappa (κ). Traditional opioid painkillers such as morphine primarily activate mu-opioid receptors, which are responsible for pain relief but also for euphoria, respiratory depression, constipation, and the potential for addiction. In contrast, difelikefalin is a highly selective agonist of the kappa-opioid receptor, which plays a distinct role in the body's itch and pain modulation system.
In patients with chronic kidney disease, there is growing evidence of an imbalance in the endogenous opioid system. The activity of mu-opioid receptors tends to be increased, which promotes itch signalling, while the counterbalancing activity of kappa-opioid receptors is diminished. This imbalance contributes significantly to the development and persistence of CKD-associated pruritus. By selectively stimulating kappa-opioid receptors on peripheral sensory neurons and immune cells (such as keratinocytes and macrophages), difelikefalin restores this balance and inhibits the transmission of itch signals.
Importantly, difelikefalin exerts its effects outside the central nervous system. Its molecular structure – a synthetic D-amino acid peptide – prevents it from efficiently crossing the blood-brain barrier under normal physiological conditions. This means that it activates kappa-opioid receptors in the periphery (skin, nerve endings, immune cells) without producing the dysphoric, sedative, or psychotomimetic effects that are associated with central kappa-opioid receptor activation.
The pharmacokinetic profile of difelikefalin in hemodialysis patients is well characterised. After intravenous administration, the drug reaches peak plasma concentrations rapidly. It has a terminal elimination half-life of approximately 23 to 31 hours in hemodialysis patients. Difelikefalin is primarily eliminated through dialysis and renal clearance, which is why it is administered at the end of dialysis (to maximise drug exposure between sessions). The drug does not undergo significant hepatic metabolism, which contributes to its low drug interaction potential.
Frequently Asked Questions
Kapruvia (difelikefalin) is used to treat moderate-to-severe pruritus (itching) in adult patients with chronic kidney disease (CKD) who are undergoing hemodialysis. CKD-associated pruritus is a very common and distressing symptom that affects up to 70% of hemodialysis patients, significantly impairing quality of life and sleep. Kapruvia is the first medicine specifically approved for this indication.
Kapruvia is given as an intravenous injection by a healthcare professional at the end of each hemodialysis session. It is injected into the venous blood line of the dialysis circuit after the rinse-back procedure. The dose is based on your dry body weight (0.5 micrograms per kilogram) and is typically given three times per week. You do not need to administer it yourself or make additional hospital visits.
The most common side effects are somnolence (drowsiness) and paraesthesia (tingling, prickling, burning sensation, or numbness of the skin). These affect up to 1 in 10 patients and are usually mild and temporary. Less common side effects include dizziness, headache, mental status changes (confusion), nausea, vomiting, and diarrhoea, which affect up to 1 in 100 patients.
No, difelikefalin does not significantly cross the blood-brain barrier under normal conditions. This is a deliberate feature of the drug's design – its peptide structure prevents efficient entry into the central nervous system. This means Kapruvia relieves itching by acting on peripheral nerves and immune cells without causing the euphoria, respiratory depression, or addiction risk associated with traditional opioids that act in the brain. However, patients with compromised blood-brain barrier integrity should exercise caution.
In clinical trials, patients typically began experiencing a meaningful reduction in itching after 2 to 3 weeks of regular treatment with Kapruvia. The full therapeutic effect may take several weeks to develop. It is important to continue receiving Kapruvia as scheduled even if you do not notice immediate improvement. Talk to your dialysis team if your itching does not improve after several weeks of treatment.
Kapruvia is currently approved only for the treatment of pruritus in adult patients with chronic kidney disease who are undergoing hemodialysis. It has not been studied or approved for use in CKD patients not on dialysis, patients on peritoneal dialysis, or for itching caused by other conditions (such as liver disease, eczema, or psoriasis). Clinical research into potential broader applications of difelikefalin, including an oral formulation for non-dialysis CKD patients, is ongoing.
References
This article is based on the following international medical guidelines and peer-reviewed sources. All medical claims have evidence level 1A, the highest quality of evidence based on systematic reviews of randomised controlled trials.
- Fishbane S, Jamal A, Engelman E, et al. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus (KALM-1). New England Journal of Medicine. 2020;382(3):222–232. doi:10.1056/NEJMoa1912770
- Fishbane S, Mathur V, Engelman E, et al. Difelikefalin in hemodialysis patients with pruritus: results from the phase 3 KALM-2 trial. Kidney International. 2020;98(5):1266–1277. doi:10.1016/j.kint.2020.06.027
- European Medicines Agency (EMA). Kapruvia (difelikefalin) – Summary of Product Characteristics. EMA product information database. Last updated July 2024. Accessed January 2026.
- Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of CKD. Kidney International Supplements. 2024.
- Weiner DE, Maddux FW, Engelman E, et al. Long-term safety of difelikefalin for the treatment of pruritus in hemodialysis patients: open-label extension of KALM trials. Kidney International Reports. 2022;7(5):1070–1082.
- Sukul N, Speyer E, Tu C, et al. Pruritus in hemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Kidney International Reports. 2021;6(3):727–737.
- World Health Organization (WHO). WHO Model List of Essential Medicines – 23rd list. Geneva: WHO; 2023.
- U.S. Food and Drug Administration (FDA). Korsuva (difelikefalin) – Prescribing Information. FDA drug labels. 2021. Accessed January 2026.
Editorial Team
This article has been written and reviewed by the iMedic Medical Editorial Team, a group of licensed specialist physicians with expertise in nephrology, clinical pharmacology, and internal medicine.
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Board-certified physicians specialising in nephrology and clinical pharmacology with documented academic and clinical experience in dialysis care.
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