Terlipressin - Treatment for Hepatorenal Syndrome Type 1

Overview:

Terlipressin is a synthetic analog of vasopressin, a hormone that helps to regulate the pressure of blood and fluid balance. It was first developed in the 1970s as an alternative to vasopressin for managing various medical conditions. Terlipressin is primarily used to treat conditions like variceal bleeding in the esophagus and stomach, hepatorenal syndrome, and septic shock. Its controlled release characteristics and reduced side effects make it a valuable medication for these conditions. Over the years, it has been refined, and its applications continue to evolve in clinical practice. Terlipressin received FDA (Food and Drug Administration) approval for the management of rapidly progressing kidney dysfunction (hepatorenal syndrome type 1) in hospitalized adult patients.

Drug Group:

Terlipressin belongs to the drug group known as vasopressors or vasopressin analogs. Terlipressin is a synthetic analog of vasopressin, a naturally occurring hormone that is crucial in regulating blood pressure, fluid balance, and vascular tone.

Available Doses and Dosage Forms:

The recommended dosing for hepatorenal syndrome may involve an initial dose of Terlipressin, commonly 0.5 to one mg (milligrams), given by intravenous injection, with subsequent doses administered at intervals, as determined by the healthcare provider.

For Patients:

What Is Hepatorenal Syndrome Type 1 (HRS-1)?

• Hepatorenal Syndrome Type 1 (HRS-1) is a critical complication that primarily affects individuals with advanced liver disease, particularly cirrhosis. In HRS-1, there is a sudden and severe deterioration of kidney function, resulting in acute kidney injury. This condition is marked by a swift advancing onset, making it a medical emergency.

• The exact mechanisms underlying HRS-1 are complex and not entirely understood, but it is closely related to the liver's role in maintaining blood flow and pressure within the circulation. In individuals with cirrhosis, changes in the liver can lead to alterations in these critical factors, ultimately impacting the function of the kidneys. The kidneys struggle to filter waste products from the blood and regulate fluid balance, resulting in a decrease in urine output and the accumulation of toxins in the bloodstream.

• Recognizing the symptoms of HRS-1 is essential for timely intervention. Common signs include reduced urine output, swelling in the legs and abdomen due to fluid retention (edema), mental confusion, and the development of ascites (abdominal fluid accumulation).

• Immediate medical attention is crucial for those suspected of having HRS-1. Diagnosis includes eliminating other potential factors of acute kidney injury and employing specific diagnostic criteria. A multidisciplinary approach often includes hepatologists and nephrologists collaborating to provide the most effective care.

• Treatment of HRS-1 aims to stabilize kidney function and improve renal blood flow. This may involve the administration of intravenous albumin to expand blood volume and vasopressor medications to constrict blood vessels and enhance blood flow to the kidneys. Additionally, strategies to support liver function and address the underlying liver disease are employed.

• In severe cases of HRS-1, where the liver disease is advanced and unlikely to improve, a liver transplant may be the only definitive treatment option. A liver transplant can restore both liver and kidney function, providing the best chance for recovery.

How Does Terlipressin Work?

Terlipressin is a medication that primarily acts as a vasopressin analog and is used in the management of certain medical conditions. Its primary mechanism of action is to constrict blood vessels and increase blood pressure. Here is how Terlipressin works:

• Vasopressin Analogue: Terlipressin is a synthetic analog of vasopressin, which is a hormone produced by the hypothalamus (in the brain) and released by the posterior pituitary gland. Vasopressin plays a crucial role in regulating blood pressure and fluid balance in the body.

• Vasoconstriction: Terlipressin acts on specific receptors in blood vessel walls, known as V1 receptors. When it binds to these receptors, it causes vasoconstriction, which means it narrows the blood vessels. This action increases peripheral vascular resistance, leading to an increase in blood pressure.

What Is the Dosage of Terlipressin?

For hepatorenal syndrome (HRS) type 1, the usual recommended dosage is Terlipressin 0.5 mg (milligrams) to two mg every four to six hours.

How Effective Is Terlipressin?

Terlipressin is considered effective for specific medical conditions, particularly in the management of acute variceal bleeding in the esophagus or upper stomach, which is often associated with liver cirrhosis and portal hypertension. It is not typically used for other conditions. Effectiveness is generally measured by the ability of Terlipressin to achieve hemostasis (stop the bleeding) and improve short-term survival in patients with acute variceal bleeding. It is often used in combination with endoscopic interventions, such as variceal band ligation. While Terlipressin is effective in this specific setting, it may not be appropriate or effective for other medical conditions. Additionally, its use requires close monitoring due to potential side effects, particularly changes in blood pressure and cardiac arrhythmias.

What Are the Things to Inform the Doctor Before Taking Terlipressin?

Before taking Terlipressin, inform the doctor about

• Allergies: Any known allergies, especially to Terlipressin or similar medications.

• Medical Conditions: Current or past heart, circulation, kidney issues, or liver conditions should be informed.

• Pregnancy and Breastfeeding: Inform the doctor if one is pregnant, planning to become pregnant, or breastfeeding.

• Medications: Inform about the list of all current medications, including over-the-counter drugs, vitamins, and supplements.

• Allergic Reactions: Any previous severe reactions to medications, especially vasopressin or related drugs, should be informed.

• Liver Function: Discuss with the doctor about the liver condition, especially cirrhosis (late stage of scarring of the liver) if relevant.

• Heart Conditions: A history of heart problems or vascular diseases.

• Kidney Function: Inform about any kidney disease or issues.

• Blood Pressure: Inform about hypertension or blood pressure-related concerns.

• Recent Surgery: Inform the doctor about recent surgical procedures, particularly abdominal surgery.

• Use of Other Vasopressors: Inform the doctor if the patient is using or has recently used other vasopressor medications.

How Is Terlipressin Administered?

Terlipressin is often administered in a healthcare setting; healthcare professionals can monitor for side effects and take action if necessary. Terlipressin is administered in the following ways:

• To create a 0.85 mg/5 mL (milligrams per milliliter) solution, mix each vial with five mL (milliliter) of 0.9 percent Sodium chloride injection. Before administering parenteral drugs, visually inspect for particles and color changes if possible.

• Administer Terlipressin via a peripheral or central line; a dedicated central line is not required. After Terlipressin administration, flush the line with sterile normal saline.

• If not given immediately, store Terlipressin between two degrees Celcius to eight degrees Celsius (36 degrees Fahrenheit to 46 degrees Fahrenheit) for up to 48 hours, avoiding freezing. Protection from light is not necessary for the reconstituted solution.

What Are the Side Effects of Terlipressin?

Terlipressin, like many medications, can cause side effects in some individuals. Common and less severe side effects may include:

• Nausea.

• Vomiting.

• Abdominal discomfort.

• Diarrhea.

• Headache.

• Dizziness.

• Increased blood pressure.

However, Terlipressin can also lead to more severe side effects that require immediate medical attention. These may include:

• Chest pain or angina.

• Shortness of breath.

• Irregular heartbeat or palpitations.

• Allergic reactions include rash, itching, or swelling of the face, lips, or tongue.

It is crucial to promptly report any unusual or severe side effects to a healthcare provider.

Dietary Considerations

While taking Terlipressin, there are no specific dietary restrictions associated with the medication itself. However, dietary considerations may be needed based on the underlying condition being treated, such as cirrhosis, which may require a low-sodium diet and proper nutrition management.

Missed Dose

In case of a missed dose of Terlipressin, contact the healthcare provider for specific instructions on how to proceed, and do not double the dose.

Overdose

If an overdose of Terlipressin occurs, the expected symptoms are likely to resemble the adverse reactions associated with therapeutic doses. In the event of an overdose, it is important to begin vigilant monitoring of vital signs, electrolyte levels, and the possibility of ischemic events, followed by the initiation of suitable symptomatic treatment.

Storage

Terlipressin is provided in single-dose vials containing 0.85 mg of Terlipressin as a sterile, preservative-free, lyophilized powder. Each vial is enclosed in a carton. It should be stored under refrigerated conditions at two degrees Celcius to eight degrees Celsius (36 degrees Fahrenheit to 46 degrees Fahrenheit), and it is important to keep it in the original carton to shield it from light before reconstitution.

For Doctors:

Indication:Terlipressin is approved for enhancing kidney function in adults diagnosed with hepatorenal syndrome, particularly in cases of rapidly declining kidney function. It is important to note that this medication may not provide significant benefits for patients whose serum creatinine levels exceed five mg/dL.

Dose:

Before starting Terlipressin treatment, it is essential to take the following steps:

1. Obtain the patient's baseline oxygen saturation (SpO2) before administering the initial Terlipressin dose.

2. Throughout the treatment course, continuously monitor the patient's oxygen saturation using pulse oximetry. Do not use Terlipressin in patients with hypoxia until their oxygen levels are normal.

3. Before initiating Terlipressin, assess the patient's acute-on-chronic liver failure (ACLF) Grade and volume status.

The recommended starting dosage for Terlipressin is 0.85 mg, administered every six hours via a slow intravenous bolus injection lasting two minutes. This dosing regimen should be followed on days one through three. On day four, adjust the dosage based on changes observed in the patient's baseline serum creatinine (SCr) values using the provided dosing chart.

What Are the Pharmacological Aspects of Terlipressin?

Pharmacodynamics:

In patients with hepatorenal syndrome type 1 (HRS-1), a single 0.85 mg dose of Terlipressin led to noticeable changes in diastolic, systolic, and mean arterial pressure (MAP), accompanied by a decrease in heart rate within five minutes of administration. These effects were sustained for at least six hours post-dosing, with the most significant alterations in blood pressure and heart rate occurring approximately 1.2 to two hours after dosing. The maximum increase in MAP was 16.2 mmHg, while the maximum decrease in heart rate was 10.6 beats per minute.

Regarding cardiac electrophysiology, a study involving 41 patients with HRS-1 who received one mg of Terlipressin acetate every six hours for up to 14 days found no clinically significant deviations from baseline in QTc interval measurements. The trial, assessed using the Fridericia correction method, reported minimal increases in the mean QTc interval, all of which were less than ten milliseconds.

Mechanism:

Terlipressin, a synthetic vasopressin analog, exhibits greater selectivity for vasopressin V1 receptors over V2 receptors, effectively acting as both a prodrug for lysine-vasopressin and an active pharmacological agent in its own right. Terlipressin's primary mechanism of action in patients with hepatorenal syndrome involves the reduction of portal hypertension and circulation within the portal vessels. This, in turn, enhances renal blood flow, effectively increasing the patient's effective arterial volume and mean arterial pressure (MAP).

Pharmacokinetics:

The pharmacokinetic parameters of Terlipressin and its primary active metabolite, lysine-vasopressin, were determined through population pharmacokinetic modeling using limited PK samples from 69 patients with HRS-1. After administering one mg intravenous injection of Terlipressin acetate, the median Cmax, AUC24h, and Cav (average concentration at steady state) for Terlipressin were 70.5 ng/mL, 123 ng×hr/mL, and 14.2 ng/mL, respectively. For lysine-vasopressin, the median Cmax, AUC24h, and Cav were 1.2 ng/mL, 11.2 ng×hr/mL, and 0.5 ng/mL, respectively. Terlipressin and lysine-vasopressin exhibited linear pharmacokinetics in healthy subjects, with plasma concentrations increasing proportionally with the administered dose.

Distribution:

• Terlipressin's volume of distribution (Vd) is 6.3 L.

• Lysine-vasopressin had a Vd of 1370 L.

Elimination:

• Terlipressin has a clearance of 27.4 L/hr.

• Lysine-vasopressin's clearance was 318 L/hr.

• In healthy subjects, no dose-dependent changes were observed in Terlipressin's elimination rate constant.

• In HRS-1 patients, Terlipressin clearance increased with body weight, while body weight did not impact lysine-vasopressin clearance.

• Terlipressin's terminal half-life is 0.9 hours, whereas lysine-vasopressin has a half-life of three hours.

Metabolism:

• Terlipressin undergoes metabolism as N-terminal glycyl residues are cleaved by tissue peptidases, releasing the active metabolite lysine-vasopressin.

• Once formed, lysine-vasopressin is metabolized by various peptidase-mediated routes in body tissue.

• Terlipressin is not metabolized in blood or plasma.

• The metabolism of Terlipressin is unlikely to be influenced by disease state or other medications due to the widespread presence of peptidases in body tissue.

Excretion:

• In healthy subjects, less than one percent of Terlipressin and less than 0.1 percent of lysine-vasopressin are excreted in urine.

Non-Clinical Toxicity

Carcinogenicity studies for Terlipressin have not been conducted. Terlipressin demonstrated no mutagenic or clastogenic effects in tests, which included an in vitro bacterial reverse mutation assay, an in vivo mouse micronucleus assay, and an in vitro mammalian cell (CHO) chromosome aberration assay. Additionally, there have been no animal studies to assess Terlipressin's impact on fertility.

Clinical Studies

In a study named CONFIRM, which was multicenter, double-blind, and placebo-controlled, the efficacy of Terlipressin was evaluated in patients with cirrhosis, ascites, and a diagnosis of HRS-1. These patients had a rapidly progressing decline in kidney function, with their serum creatinine (SCr) levels reaching more than or equal to 2.25 mg/dL and showing a trajectory for SCr to double over two weeks. Patients who did not exhibit a sustained improvement in renal function (defined as less than 20 percent decrease in serum creatinine and serum creatinine more than or equal to 2.25 mg/dL) 48 hours after diuretic withdrawal and albumin administration were eligible for the study.

The study enrolled 300 patients, predominantly middle-aged (median age 55 years), with 60 percent being male and 90 percent White. At baseline, 40 percent had alcoholic hepatitis, and 19 percent had ACLF Grade 3. The mean serum creatinine was 3.5 mg/dL, and the mean MELD (model for end-stage liver disease) score was 33.

Patients were randomized into two groups, with 199 receiving Terlipressin and 101 receiving a placebo. The treatment consisted of one mg of Terlipressin acetate (equivalent to Terlipressin 0.85 mg) or a placebo every six hours via intravenous bolus injection over two minutes for a maximum of 14 days. If SCr did not decrease by at least 30 percent from the baseline on day four, the dose was increased to two mg of Terlipressin acetate (equivalent to Terlipressin 1.7 mg) every six hours. Treatment was discontinued if SCr remained at or above the baseline value on day four. Both groups received albumin therapy during the study.

The primary endpoint measured the rate of verified HRS reversal, requiring two consecutive serum creatinine values of less than or equal to 1.5 mg/dL taken at least two hours apart by Day 14 or discharge. To be part of this analysis, patients had to be alive and not receive renal replacement therapy (e.g., dialysis) for at least ten days after achieving verified HRS reversal.

Patients treated with Terlipressin achieved a greater proportion of verified HRS reversal compared to those in the placebo group. The results are summarized as follows:

• Terlipressin: 29.1 percent achieved Verified HRS Reversal.

• Placebo: 15.8 percent achieved Verified HRS Reversal.

These results indicate the efficacy of Terlipressin in improving kidney function in patients with HRS-1.

What Are the Contraindications of Terlipressin?

Terlipressin should not be used in patients with hypoxia or worsening respiratory symptoms. It is also contraindicated in individuals with ongoing coronary, peripheral, or mesenteric ischemia.

Warnings and Precautions:

The warnings and precautions associated are as follows:

Respiratory Dysfunction

• In the primary trial, 14 percent of Terlipressin patients experienced severe respiratory issues compared to five percent on placebo.

• Assess oxygen levels before starting Terlipressin, avoid hypoxic patients, and monitor for respiratory changes.

• Discontinue Terlipressin if hypoxia or worsened respiratory symptoms occur.

• Patients with fluid overload are at risk and should manage their fluids carefully.

Liver Transplant Ineligibility

• Terlipressin-related reactions may disqualify patients from liver transplantation.

• Evaluate the balance of benefits and risks, especially in high-priority transplant cases.

Ischemic Events

• Terlipressin may cause cardiac, cerebrovascular, peripheral, or mesenteric ischemia.

• Avoid Terlipressin in patients with a history of severe heart or vascular conditions.

• Discontinue Terlipressin if ischemic symptoms appear.

Fetal Risk

• Terlipressin use during pregnancy may harm the fetus due to uterine contractions and endometrial ischemia.

• Pregnant patients should be informed about the risks.

What Are the Drug Interactions of Terlipressin?

Studies conducted in human liver microsomes in vitro indicated that Terlipressin does not exhibit significant inhibitory or inductive effects on CYP enzymes, whether in direct action, time dependence, or metabolism. Furthermore, the evidence suggests that Terlipressin is not a substantial inhibitor or substrate of human ABC and SLC transporters. Therefore, it is expected that Terlipressin will not engender significant drug-drug interactions.

Specific Considerations:

• Pregnancy: Terlipressin may cause fetal harm when given to pregnant women. Limited studies suggest uterine contractions and endometrial ischemia in early pregnancy. Specific risks for birth defects or miscarriage remain uncertain, so patients must be informed of potential fetal risks.

• Animal Studies: Animal studies show reduced uterine and placental blood flow in guinea pigs at lower-than-recommended doses. In rabbits, Terlipressin caused embryotoxicity and teratogenic effects.

• Lactation: No data on Terlipressin in human or animal milk. Consider breastfeeding benefits against potential risks to the infant.

• Pediatric Use: Terlipressin's safety and effectiveness in pediatric patients have not been established.

• Geriatric Use: No notable differences in safety or effectiveness were observed in elderly patients in clinical studies.

• Hepatic Impairment: No dosage adjustment is required for patients with hepatic impairment.