Terlipressin (DB02638): A Comprehensive Monograph on Pharmacology, Clinical Efficacy, and Safety

Section 1: Executive Summary & Drug Identification

Terlipressin is a potent synthetic analogue of the endogenous hormone vasopressin, classified as a vasopressin receptor agonist. It functions as a prodrug, undergoing slow enzymatic conversion in the body to its active metabolite, lypressin (lysine-vasopressin). This unique pharmacokinetic profile provides a sustained vasoconstrictive effect, which forms the basis of its therapeutic utility. For decades, terlipressin has been a cornerstone of therapy outside the United States for life-threatening conditions such as acute esophageal variceal bleeding and hepatorenal syndrome (HRS). In 2022, it became the first and only medication approved by the U.S. Food and Drug Administration (FDA) to improve kidney function in adults with HRS involving a rapid reduction in kidney function (HRS-AKI), a condition with an otherwise dismal prognosis.

The clinical profile of terlipressin is defined by a critical balance between its demonstrated efficacy and significant safety concerns. Its primary mechanism involves preferential agonism at V1 vasopressin receptors, leading to powerful splanchnic vasoconstriction. This action directly counteracts the core pathophysiology of HRS—profound vasodilation in the splanchnic circulation—thereby increasing systemic vascular resistance, raising mean arterial pressure, and improving renal perfusion. However, this same potent vasoconstriction, coupled with effects on V2 receptors, gives rise to considerable risks, most notably serious or fatal respiratory failure, ischemic events affecting cardiac and other tissues, and a risk of sepsis.

The regulatory journey of terlipressin in the United States was complex, culminating in an approval that carries a stringent Boxed Warning and specific limitations of use. Both the FDA and the European Medicines Agency (EMA) have independently converged on similar risk mitigation strategies, underscoring a global consensus on the need for careful patient selection and meticulous monitoring. Comparative analyses show terlipressin to be at least as effective as, and in some high-acuity populations superior to, alternatives like norepinephrine for HRS, and comparable to octreotide for variceal bleeding. Despite a high acquisition cost, pharmacoeconomic models suggest it is a cost-effective intervention for HRS in the U.S. hospital setting, primarily through the avoidance of expensive downstream care like intensive care unit stays and renal replacement therapy. This report provides an exhaustive analysis of terlipressin, covering its chemical properties, pharmacology, clinical evidence, complex safety profile, and its place in modern critical care and hepatology.

Table 1: Drug Identification and Key Properties

Property	Details	Source(s)
Generic Name	Terlipressin	1
DrugBank ID	DB02638	3
CAS Number	14636-12-5	3
Type	Biotech, Protein-based therapy (Hormone)	4
Chemical Formula	C52​H74​N16​O15​S2​	1
Molecular Weight	1227.37 g/mol	5
ATC Code	H01BA04	7
U.S. Brand Name	Terlivaz	1
Select International Brand Names	Glypressin, Remestyp, Variquel	1
Drug Class	Vasopressin Receptor Agonist, Antidiuretic Hormone Analog	1

Section 2: Chemical Properties and Formulation

Molecular Structure and Description

Terlipressin is a synthetic polypeptide and a structural analogue of vasopressin, the natural hormone of the posterior pituitary gland.[3] It is specifically defined as a triglycyl-lysine derivative of vasopressin, composed of 12 amino acids.[12] Its chemical structure differs from native vasopressin in two key ways: first, the arginine residue at position 8 is substituted with lysine; second, three glycine residues are attached as a side chain to the N-terminal amino group of the cysteine residue at position 1.[12]

The complete amino acid sequence of terlipressin is Gly-Gly-Gly-c-Pro-Lys-Gly-NH2.[8] A defining feature of its structure is the cyclic component formed by a disulfide bridge between the cysteine residues at positions 4 and 9 (relative to the vasopressin core structure).[8] This cyclic structure is essential for its biological activity. The full chemical name is glycyl-glycyl-glycyl-L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparagyl-L-cysteinyl-L-prolyl-L-lysyl-glycinamide (4->9)-disulfide.[3] The molecular formula is

C52​H74​N16​O15​S2​, and its molecular weight is approximately 1227.37 g/mol.[1]

Formulation and Physical Properties

Terlipressin is commercially available for clinical use as a sterile, white, lyophilized (freeze-dried) powder intended for reconstitution and subsequent intravenous administration.[2] It is supplied in single-dose vials.[2] In the United States, under the brand name Terlivaz, each vial contains 0.85 mg of terlipressin free base, which is stoichiometrically equivalent to 1 mg of terlipressin acetate.[13] The use of an acetate salt form is common, as it enhances the stability and solubility of the peptide for pharmaceutical formulation.[5]

Before administration, the lyophilized powder is reconstituted, typically with 5 mL of 0.9% Sodium Chloride Injection, to yield a clear solution.[15] As a solid, terlipressin has a melting point greater than 170°C, at which it decomposes.[8] Unopened vials must be stored under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light.[15] Once reconstituted, the solution is stable for up to 48 hours under refrigeration and does not require light protection.[19] Its solubility is described as slight in DMSO and methanol.[8]

Section 3: Clinical Pharmacology

3.1 Mechanism of Action

The pharmacological effects of terlipressin are complex, stemming from its nature as a prodrug and its interactions with the vasopressin receptor system.[3]

Prodrug Activation

Terlipressin itself is a pharmacologically inactive pro-hormone.[8] Following intravenous administration, it circulates in the body and undergoes slow, enzymatic cleavage by tissue peptidases, specifically exopeptidases.[3] These enzymes sequentially remove the three N-terminal glycyl residues, which releases the biologically active metabolite, lypressin (also known as lysine-vasopressin).[3] This metabolic conversion does not occur in the blood or plasma but rather in various body tissues, a process that is ubiquitous and therefore unlikely to be significantly affected by specific organ dysfunction (e.g., liver or kidney disease) or by drugs that modulate common metabolic pathways like the cytochrome P450 system.[3]

Receptor Selectivity

As an analogue of vasopressin, lypressin exerts its effects by acting as an agonist at vasopressin receptors, which are G-protein coupled receptors. There are three main subtypes: V1a, V1b, and V2.[4] Terlipressin (via its active metabolite lypressin) demonstrates agonist activity at all three, but with clinically important selectivity. It exhibits approximately twice the selectivity for V1 receptors compared to V2 receptors.[4]

• V1 Receptors (V1a): These receptors are predominantly located on vascular smooth muscle cells. Their activation leads to vasoconstriction by increasing intracellular calcium levels.[4] Terlipressin's primary therapeutic effects are mediated through potent V1a receptor agonism, particularly in the splanchnic vascular bed (the blood vessels supplying the abdominal organs).[4]
• V2 Receptors: These are mainly found on the basolateral membrane of the distal tubules and collecting ducts in the kidneys. Their activation is responsible for the antidiuretic effect of vasopressin, promoting water reabsorption and regulating water homeostasis.[4] Terlipressin's action at V2 receptors is less pronounced than its V1 action.
• V1b Receptors: These are found in the anterior pituitary and are involved in the release of adrenocorticotropic hormone (ACTH), though this effect is less central to terlipressin's primary clinical uses.[4]

Hemodynamic Effects

The therapeutic utility of terlipressin is rooted in its profound hemodynamic effects. In conditions like hepatorenal syndrome (HRS) and portal hypertension, the underlying pathophysiology involves severe splanchnic arterial vasodilation, which leads to a decrease in effective circulating blood volume and a drop in mean arterial pressure (MAP).[4] Terlipressin directly counteracts this by causing intense vasoconstriction in the splanchnic circulation.[4] This action reduces blood flow into the portal venous system, thereby decreasing portal pressure, and simultaneously shunts blood back into the systemic circulation.[2] The net result is an increase in the effective arterial blood volume and a rise in systemic vascular resistance, leading to a significant increase in diastolic, systolic, and mean arterial pressure.[3] In patients with HRS-1, these cardiovascular effects are observed within five minutes of dosing and are maintained for at least six hours, with the maximum effect on blood pressure occurring 1.2 to two hours post-dose.[3] This increase in blood pressure is typically accompanied by a baroreceptor-mediated reflex decrease in heart rate.[3]

3.2 Pharmacokinetics (ADME)

The pharmacokinetic profile of terlipressin is unique and central to its clinical advantages over direct-acting vasopressors like native vasopressin. A key aspect is the distinction between the pharmacokinetics of the parent prodrug (terlipressin) and its active metabolite (lypressin).

The "Slow-Release" Pharmacokinetic Advantage

A fundamental challenge with using native vasopressin is its extremely short biological half-life, which necessitates continuous intravenous infusion to maintain a therapeutic effect. This requirement often restricts its use to intensive care unit (ICU) settings and carries the risk of rebound hypotension if the infusion is stopped abruptly. Terlipressin was designed to overcome these limitations. Its nature as a prodrug that is slowly cleaved in tissues creates a "slow-release" system for its active metabolite, lypressin.[3] This is evident in the starkly different pharmacokinetic parameters of the two molecules. Terlipressin itself is cleared rapidly from the plasma, with a terminal half-life of only about 0.9 hours.[3] However, as it is cleared, it is continuously converted to lypressin, which has a much longer terminal half-life of 3.0 hours.[3] This extended presence of the active metabolite allows for a sustained duration of action of 4 to 6 hours from a single bolus injection.[8] This profile avoids the sharp concentration peaks that can lead to toxicity and the rapid troughs that can cause loss of efficacy, thereby maintaining a smoother, more prolonged vasoconstrictive effect. This pharmacokinetic behavior provides significant clinical convenience, allowing for intermittent bolus administration every 4 to 6 hours, which can be managed on a general hospital floor and does not strictly require a central venous catheter.[3]

Table 2: Pharmacokinetic Parameters of Terlipressin and Lypressin

Parameter	Terlipressin (Prodrug)	Lypressin (Active Metabolite)	Source(s)
Median Cmax​ (1 mg dose)	70.5 ng/mL	1.2 ng/mL	4
Median AUC24h​ (1 mg dose)	123 ng·hr/mL	11.2 ng·hr/mL	4
Volume of Distribution (Vd​)	6.3 L	1370 L	4
Terminal Half-life (t1/2​)	0.9 hours	3.0 hours	3
Clearance	27.4 L/hr	318 L/hr	4

Absorption, Distribution, Metabolism, and Excretion (ADME)

• Absorption: Terlipressin is administered intravenously, resulting in 100% bioavailability. Following a 1 mg IV dose in HRS-1 patients, the median peak plasma concentration (Cmax​) of terlipressin is 70.5 ng/mL, while the Cmax​ of the resulting lypressin is much lower at 1.2 ng/mL, reflecting the slow conversion process. The pharmacokinetics are linear, with plasma concentrations increasing proportionally to the administered dose.[4]
• Distribution: The volume of distribution (Vd​) for terlipressin is small at 6.3 L, indicating it is largely confined to the intravascular space.[4] In stark contrast, the Vd​ for lypressin is extremely large at 1370 L, suggesting extensive distribution into body tissues where it exerts its pharmacological effects.[4]
• Metabolism: As detailed previously, terlipressin is metabolized in tissues throughout the body by peptidases into its active form, lypressin. Lypressin itself is then further metabolized via various peptidase-mediated pathways.[3]
• Excretion: Elimination of the parent drug and active metabolite is not primarily renal. Studies in healthy subjects show that less than 1% of the administered terlipressin dose and less than 0.1% of lypressin are excreted unchanged in the urine, underscoring the completeness of its tissue-based metabolism.[4]

Section 4: Clinical Application in Hepatorenal Syndrome (HRS)

4.1 Pathophysiological Rationale and Place in Therapy

Hepatorenal syndrome (HRS) is a devastating complication of advanced liver disease, particularly cirrhosis with ascites. It is defined as a form of functional renal failure characterized by a rapid decline in kidney function in the absence of intrinsic kidney pathology.[20] The underlying pathophysiology is driven by extreme portal hypertension, which leads to profound vasodilation in the splanchnic arterial circulation. This splanchnic vasodilation "traps" a large portion of the circulatory volume, causing a severe reduction in effective arterial blood volume. In response, the body activates potent vasoconstrictor systems, such as the renin-angiotensin-aldosterone system and the sympathetic nervous system, leading to intense renal vasoconstriction and a dramatic fall in renal perfusion and glomerular filtration rate.[4]

Terlipressin is uniquely suited to target this core pathophysiological mechanism. By acting as a potent V1 receptor agonist, it induces powerful vasoconstriction in the splanchnic vascular bed.[4] This action reverses the splanchnic vasodilation, increases systemic vascular resistance, and redirects blood flow back into the effective systemic circulation, thereby increasing mean arterial pressure (MAP) and improving blood flow to the kidneys.[2]

On September 14, 2022, terlipressin (as Terlivaz) became the first and only therapy approved by the U.S. Food and Drug Administration (FDA) for the indication "to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function".[13] This indication corresponds to the condition historically known as HRS Type 1, and now more accurately termed HRS-Acute Kidney Injury (HRS-AKI).[20] Reflecting its robust evidence base, terlipressin is recommended as a first-line agent for HRS-AKI in combination with albumin by major clinical practice guidelines, including those from the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL).[20]

4.2 Pivotal Clinical Evidence: The CONFIRM Trial (NCT02770716)

The FDA approval of terlipressin was primarily based on the results of the Phase 3 CONFIRM trial, the largest prospective, randomized, double-blind, placebo-controlled study ever conducted for this indication in North America.[22]

Trial Design

The CONFIRM trial enrolled 300 adult patients with cirrhosis and HRS-1 (diagnosed using the older criteria) in the U.S. and Canada.[13] Patients were randomized in a 2:1 ratio to receive either terlipressin (n=199) or placebo (n=101). The study drug was administered as an intravenous bolus every 6 hours for a maximum of 14 days. The initial dose of terlipressin was 0.85 mg, which could be doubled on day 4 if the patient's renal response was inadequate. All patients in both arms were eligible to receive albumin concomitantly, which is the standard of care.[13]

Efficacy Outcomes

The trial successfully met its primary endpoint, which was "Verified HRS Reversal." This was a composite endpoint rigorously defined as achieving two consecutive serum creatinine (SCr) values of 1.5 mg/dL or less, at least two hours apart, while on treatment, followed by survival without the need for renal replacement therapy (RRT, e.g., dialysis) for at least 10 days after achieving this renal recovery.[13] The results demonstrated a clear and statistically significant benefit for terlipressin.

Table 3: Summary of Efficacy Outcomes from the CONFIRM Trial

Endpoint	Terlipressin + Albumin (n=199)	Placebo + Albumin (n=101)	p-value	Source(s)
Verified HRS Reversal (Primary)	29% - 32%	16% - 17%	0.012	13
HRS Reversal (SCr ≤1.5 mg/dL)	39%	18%	<0.001	25
RRT-free at Day 30	32%	16%	0.003	13

As shown in the table, nearly twice as many patients in the terlipressin group achieved the primary endpoint compared to the placebo group. Terlipressin was also superior in multiple key secondary endpoints, including the proportion of patients achieving HRS reversal at any point during treatment and the proportion of patients who had an SCr value of 1.5 mg/dL or less at day 14 or discharge.[13]

Safety Outcomes and Controversy

Despite the positive efficacy findings, the trial was marked by a significant and concerning safety signal. The data revealed a substantially higher incidence of serious or fatal respiratory failure in the terlipressin arm compared to the placebo arm. Respiratory failure was reported in 15.5% of terlipressin-treated patients versus 7% in the placebo group, with fatal respiratory adverse events occurring in 8.5% of the terlipressin arm versus just 1% in the placebo group.[15] This adverse event profile became a central point of controversy during the regulatory review process.[21] Some post-hoc analyses and editorials have debated whether the high volumes of albumin administered to patients in the trial (a mean of nearly 200 g in the terlipressin group) may have contributed to fluid overload and exacerbated the risk of respiratory failure, potentially obscuring the drug's true benefit-risk profile.[16]

4.3 U.S. Regulatory Journey and FDA Approval

The path to terlipressin's approval in the United States was exceptionally long and fraught with regulatory hurdles, reflecting the deep-seated concerns about its safety profile.

Timeline and Setbacks

The first attempts to gain approval began over a decade earlier, with an initial New Drug Application (NDA) for a formulation called Lucassin being filed in 2009.[2] After Mallinckrodt acquired the drug, a new NDA was submitted based on the CONFIRM trial data. In July 2020, an FDA Advisory Committee narrowly voted 8 to 7 to recommend approval, a split decision that highlighted the expert community's division over the drug's risk-benefit balance.[2]

Following this contentious meeting, the FDA issued a Complete Response Letter (CRL) in September 2020, declining to approve the drug and requesting more information to demonstrate that its benefit outweighed its risks, particularly the risk of respiratory failure.[2] After further discussions with the agency, Mallinckrodt prepared to resubmit the application. However, a second CRL was issued in February 2022 for a non-clinical reason: the FDA was unable to conduct a timely inspection of a newly designated third-party packaging and labeling facility.[26]

Final Approval and Risk Mitigation

Mallinckrodt resubmitted the NDA in June 2022.[2] On September 14, 2022, the FDA finally granted approval for Terlivaz.[13] This approval was not unconditional; it was accompanied by a stringent Risk Evaluation and Mitigation Strategy (REMS). The final product label includes a prominent Boxed Warning—the FDA's most serious type of warning—for serious or fatal respiratory failure, along with specific limitations of use and mandatory monitoring requirements.[21]

The approval of Terlivaz serves as a compelling case study in modern regulatory decision-making for diseases with high unmet need. The FDA was faced with a difficult choice: on one hand, HRS is a rapidly fatal condition with no other approved pharmacological treatments in the U.S., creating immense pressure to provide a new therapeutic option.[13] On the other hand, the pivotal trial data, while showing a statistically significant benefit in renal function, also revealed a clear and life-threatening risk.[21] The agency's ultimate decision represents a carefully calibrated compromise. It allows access to the only available therapy for these critically ill patients but imposes strict guardrails designed to mitigate the known harms. The manufacturer developed a risk mitigation strategy, based on post-hoc analyses of the CONFIRM trial, that identified patient subgroups at highest risk. The FDA concluded that while this strategy had not been prospectively tested, it was a reasonable approach to manage the risk.[21] The final label, with its specific contraindications (e.g., for patients with SCr >5 mg/dL) and mandated monitoring (e.g., continuous pulse oximetry), is the direct embodiment of this regulatory balance, seeking to maximize benefit in a narrow, carefully selected patient population while minimizing risk.[21]

Section 5: Clinical Application in Esophageal Variceal Bleeding

While new to the U.S. market for HRS, terlipressin has a long and established history internationally as a primary treatment for another life-threatening complication of portal hypertension: acute esophageal variceal bleeding.

5.1 Evidence Base and Hemodynamic Effects

Acute variceal hemorrhage is a medical emergency caused by the rupture of dilated veins (varices) in the esophagus or stomach, which form as a consequence of severe portal hypertension in patients with liver cirrhosis.[14] The primary goal of pharmacotherapy is to urgently reduce portal pressure to control the bleeding.[12]

Terlipressin achieves this by potently constricting the splanchnic arterioles, which reduces blood flow into the portal venous system and consequently lowers the hepatic venous pressure gradient (HVPG), the gold standard for measuring portal pressure.[1] Numerous clinical trials and meta-analyses conducted over several decades have validated its efficacy for this indication.[1] It has been shown to be superior to placebo and has been extensively compared to other vasoactive agents, such as somatostatin and its analogue, octreotide.[28] While the overall efficacy in controlling bleeding and improving short-term survival is often found to be comparable to octreotide, studies focusing on hemodynamics have shown that terlipressin's effect on reducing HVPG is more potent and sustained over time. One study demonstrated that terlipressin's pharmacodynamic effect persisted for longer than that of even high-dose octreotide, highlighting a key mechanistic advantage.[28]

5.2 International Guideline Recommendations

Reflecting this extensive evidence base, terlipressin has been approved and considered a standard of care for acute variceal bleeding in Europe and on at least five continents for more than 30 years.[13] International clinical practice guidelines consistently recommend the early administration of a vasoactive drug in all patients with suspected variceal bleeding, often even before diagnostic endoscopy is performed.[28] Terlipressin is listed as one of the first-line vasoactive agents of choice for this purpose, alongside somatostatin and octreotide.[32]

Section 6: Dosing and Administration

The dosing of terlipressin is highly dependent on the clinical indication and, in the case of HRS, involves a response-guided titration strategy. Administration is always via intravenous injection.

Table 4: Dosing Regimens for Major Indications

Indication	Phase of Treatment	IV Bolus Dose	Continuous IV Infusion	Duration	Source(s)
Hepatorenal Syndrome (U.S. FDA-Approved)	Days 1-3	0.85 mg every 6 hours	Not FDA-approved	Up to 14 days total	13
	Day 4 Assessment	If SCr decrease <30%, increase to 1.7 mg q6h. If SCr ≥ baseline, discontinue.			13
Acute Variceal Bleeding (International)	Initial Dose	2 mg	An alternative approach	Until bleeding controlled	32
	Maintenance	1-2 mg every 4-6 hours	May reduce side effects	Typically 48-72 hours	16

6.1 Hepatorenal Syndrome (FDA-Approved Regimen)

The FDA-approved dosing regimen for HRS-AKI is structured and requires close monitoring of renal function to guide therapy.[19]

• Initial Dosing (Days 1-3): Treatment is initiated with 0.85 mg of terlipressin administered as a slow intravenous bolus over 2 minutes, every 6 hours.[13]
• Day 4 Assessment and Dose Adjustment: On the fourth day of therapy, the patient's serum creatinine (SCr) is assessed relative to their baseline value (the last available SCr before starting treatment).
• If the SCr has decreased by less than 30% from baseline, the dose should be increased to 1.7 mg IV every 6 hours.
• If the SCr has decreased by 30% or more, the dose should be continued at 0.85 mg IV every 6 hours.
• If the SCr is at or above the baseline value, this indicates a lack of response, and terlipressin should be discontinued.[13]
• Duration of Therapy: If not discontinued for non-response, treatment is continued until 24 hours after the patient achieves two consecutive SCr values of 1.5 mg/dL or less (measured at least 2 hours apart), or for a maximum total duration of 14 days.[13]

6.2 Esophageal Variceal Bleeding (Guideline-Based Regimens)

The dosing for acute variceal bleeding, based on international guidelines and decades of practice, is typically more straightforward.

• Initial Dose: An initial loading dose of 2 mg is given as an IV bolus as soon as variceal bleeding is suspected.[32]
• Maintenance Dose: This is followed by maintenance doses of 1-2 mg IV every 4 to 6 hours.[33] Therapy is generally continued until bleeding has been controlled for 24 hours, with a typical total duration of 48 to 72 hours.[32]

6.3 Continuous Infusion vs. Bolus Injection

An important emerging concept in terlipressin administration is the use of continuous intravenous infusion as an alternative to the traditional intermittent bolus injections.[10] This approach has been formally recommended for consideration by the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) and is supported by several guidelines and studies.[16] The primary rationale is safety and tolerability. Bolus injections lead to high peak plasma concentrations of the drug, which may be associated with a higher risk of ischemic and other adverse events. A continuous infusion can achieve and maintain a therapeutic steady-state concentration with a lower total daily dose, potentially reducing the incidence and severity of side effects while preserving efficacy.[16]

Section 7: Safety Profile and Risk Management

The clinical use of terlipressin is fundamentally constrained by its significant safety concerns. A thorough understanding of its adverse event profile, contraindications, and the required risk management strategies is essential for any clinician prescribing the drug.

7.1 Boxed Warning: Serious or Fatal Respiratory Failure

In the United States, the prescribing information for Terlivaz carries a Boxed Warning for the risk of serious or fatal respiratory failure.[15] This is the most stringent warning mandated by the FDA and reflects the gravity of the risk identified in the CONFIRM trial.

• High-Risk Populations: The warning explicitly states that patients with pre-existing intravascular volume overload or those with severe acute-on-chronic liver failure (ACLF Grade 3) are at a significantly increased risk.[22]
• Mandatory Monitoring and Mitigation: To manage this risk, the label mandates a strict protocol. Before initiating therapy, clinicians must obtain a baseline oxygen saturation (SpO2) level. Terlipressin must not be started in patients who are hypoxic (defined as SpO2 <90%) until their oxygenation improves. During treatment, all patients must be monitored for hypoxia using continuous pulse oximetry. If a patient's SpO2 decreases below 90% at any point, terlipressin must be discontinued immediately.[15]

7.2 Contraindications and Ischemic Risks

The vasoconstrictive power of terlipressin underlies both its efficacy and its most dangerous side effects.

• Absolute Contraindications: Terlipressin is absolutely contraindicated in two groups of patients: (1) those currently experiencing hypoxia or who have worsening respiratory symptoms, and (2) those with evidence of ongoing coronary, peripheral, or mesenteric ischemia.[1]
• Ischemic Events: As a potent vasoconstrictor, terlipressin can cause or exacerbate ischemia in any vascular bed, leading to potentially severe cardiac (e.g., myocardial infarction), cerebrovascular (e.g., stroke), peripheral, or mesenteric ischemic events.[2] For this reason, its use should be avoided in patients with a known history of severe cardiovascular conditions or significant cerebrovascular or ischemic disease.[15] If any signs or symptoms suggestive of an ischemic event occur during treatment, the drug must be discontinued.[15]

Table 5: Profile of Common and Serious Adverse Events (Incidence from CONFIRM Trial)

Adverse Reaction	Terlipressin (n=199) Incidence %	Placebo (n=101) Incidence %	Source(s)
Abdominal pain	19.5%	6.1%	15
Nausea	16.0%	10.0%	15
Respiratory failure	15.5%	7.0%	15
Diarrhea	13.0%	7.0%	15
Dyspnea (Shortness of breath)	12.5%	5.0%	15
Fluid overload	8.5%	-	15
Sepsis	5.5%	-	15
Ischemia-related events	4.5%	-	15

7.4 European Medicines Agency (EMA) Safety Review

The safety signals from the CONFIRM trial prompted a formal safety review by European regulators. In January 2022, at the request of the Danish medicines agency, the EMA initiated an Article 31 referral to assess the benefit-risk balance of terlipressin for HRS.[39] The review was conducted by the Pharmacovigilance Risk Assessment Committee (PRAC).

The PRAC's review confirmed the findings from the CONFIRM trial, noting a higher-than-previously-reported risk of respiratory failure (11%) and identifying a new risk of sepsis or septic shock, which occurred in 7% of patients in the terlipressin arm of the study compared to none in the placebo group.[10]

In response, in November 2022, the EMA endorsed a set of new recommendations to mitigate these risks. These measures demonstrate a remarkable convergence with the FDA's own conclusions. The EMA recommended that terlipressin should be avoided in patients with:

1. Advanced renal dysfunction, specifically a baseline serum creatinine ≥ 5.0 mg/dL (442 µmol/L).
2. Advanced liver disease, defined as ACLF Grade 3 and/or a Model for End-Stage Liver Disease (MELD) score ≥39.[10]

These recommendations highlight a global regulatory consensus that has emerged around the drug's safety profile. Despite operating through different regulatory frameworks—the FDA incorporating warnings into an initial approval and the EMA adding them via a post-approval safety review—both agencies independently analyzed the same core evidence and arrived at nearly identical, specific, and quantitative criteria for identifying patients in whom the risks of terlipressin likely outweigh the benefits. This "convergent evolution" of regulatory guardrails strongly validates the importance of these specific risk factors (severe renal dysfunction, severe ACLF) and underscores that they are data-driven conclusions critical for the safe use of the medication worldwide.

7.5 Special Populations

• Pregnancy: Terlipressin is contraindicated during pregnancy.[27] Its mechanism of action includes inducing uterine contractions and increasing intrauterine pressure, which can decrease uterine blood flow.[41] Animal studies have demonstrated that it is both embryotoxic and teratogenic, causing spontaneous abortion, increased fetal resorptions, and fetal malformations even at doses lower than the maximum recommended human dose.[15]
• Liver Transplant Eligibility: A critical and unique warning associated with terlipressin relates to its potential impact on a patient's candidacy for liver transplantation, which is the only definitive cure for HRS.[42] The prescribing information warns that terlipressin-related adverse reactions, particularly severe respiratory failure or ischemic events, may render a patient ineligible for a liver transplant if they are on the waiting list.[15] This creates a difficult clinical dilemma. For patients with very advanced liver disease and high priority for transplant (e.g., MELD score ≥35), the potential short-term benefit of improved kidney function from terlipressin may not outweigh the risk of an adverse event that could disqualify them from receiving a life-saving organ.[15]

Section 8: Comparative and Economic Analysis

8.1 Comparative Efficacy

Terlipressin vs. Norepinephrine for HRS

In the absence of an FDA-approved therapy prior to 2022, norepinephrine administered as a continuous infusion in an ICU setting became a common off-label treatment for HRS-AKI in the United States.[21] It is still recommended as an alternative to terlipressin in many guidelines.[24]

A number of randomized controlled trials (RCTs) and several meta-analyses have compared the two agents head-to-head. The overall picture is nuanced. A 2024 meta-analysis found that terlipressin was associated with a numerically higher rate of HRS reversal (47.9% vs. 39.9%) and a lower 1-month mortality rate (50.7% vs. 63.5%) compared to norepinephrine, but these differences did not achieve statistical significance in the pooled analysis of the general HRS-AKI population.24 An earlier meta-analysis from 2014 similarly found no significant difference in HRS reversal or mortality.44

However, in the specific, high-acuity population of patients with ACLF, an open-label RCT published in 2020 found terlipressin to be significantly superior to norepinephrine. In this trial, terlipressin led to a higher rate of HRS reversal (40% vs. 16.7%; p=0.004) and significantly improved 28-day survival (48.3% vs. 20%; p=0.001).[45] This suggests that terlipressin's benefits may be more pronounced in the sickest patients.

The adverse event profiles also differ. Terlipressin is more commonly associated with gastrointestinal side effects like abdominal pain and diarrhea, as well as ischemic complications. Norepinephrine is associated with a higher incidence of cardiovascular adverse events like chest pain and arrhythmias.[24] The choice between the two agents requires a careful consideration of the patient's specific clinical status, comorbidities, and the logistical requirements of care, as norepinephrine necessitates an ICU bed and central venous access.[24]

Table 6: Head-to-Head Comparison: Terlipressin vs. Norepinephrine for HRS

Metric	Terlipressin	Norepinephrine	Source(s)
HRS Reversal Rate	Numerically higher, but not statistically significant in most meta-analyses. Superior in ACLF.	Lower, especially in ACLF.	24
Mortality Rate	Numerically lower, but not statistically significant in most meta-analyses. Lower in ACLF.	Higher, especially in ACLF.	24
Common Adverse Events	Abdominal pain, diarrhea, ischemia	Chest pain, arrhythmias, ventricular ectopy	24
Setting of Care	Can be used on general medical floor or ICU	Requires ICU and central line	23

Terlipressin vs. Octreotide for Esophageal Variceal Bleeding

For the treatment of acute variceal bleeding, terlipressin's main comparator is octreotide (a somatostatin analogue). Numerous studies have compared these agents. While terlipressin has been shown to produce a more prolonged and potent reduction in portal pressure (HVPG) [28], most large head-to-head trials and meta-analyses have concluded that their clinical efficacy in terms of controlling acute hemorrhage, preventing re-bleeding, and affecting in-hospital survival is largely comparable.[29] Some network meta-analyses have suggested that octreotide may have a slightly more favorable safety profile, with a lower risk of adverse events.[30]

8.2 Pharmacoeconomics

The introduction of Terlivaz in the U.S. came with a high acquisition cost, raising important questions about its value and cost-effectiveness. However, economic analyses from the U.S. hospital perspective have revealed a compelling value proposition that extends beyond the initial drug price. The true economic benefit of terlipressin appears to be rooted in its ability to avoid substantial downstream healthcare costs by being more clinically effective than its alternatives.

A cohort decision-tree model compared the costs and outcomes of treating HRS-AKI with terlipressin + albumin versus two common off-label regimens: norepinephrine + albumin and midodrine/octreotide + albumin.[47] The model incorporated costs of the drugs, hospital and ICU stays, RRT, and transplants. While terlipressin had a higher pharmacy cost than midodrine/octreotide, its total hospitalization cost was lower than that of norepinephrine. This was primarily driven by a massive difference in ICU-related costs, as norepinephrine requires an ICU setting while terlipressin often does not.[47]

The most telling metric was the "cost per complete response" (i.e., cost per HRS reversal). Here, the superior clinical efficacy of terlipressin created a dramatic separation. The response rate for terlipressin was 36.2%, compared to 19.1% for norepinephrine and a mere 3.1% for midodrine/octreotide.[47] This difference in efficacy means that far more patients need to be treated with the less effective therapies to achieve one successful outcome, driving up their effective cost. The analysis concluded that the cost per complete response for terlipressin was approximately half that of norepinephrine and a tenth that of midodrine/octreotide. This demonstrates that investing in a more expensive but significantly more effective drug upfront can lead to profound overall cost savings for the healthcare system by reducing the need for the most expensive components of care for these patients: ICU stays and dialysis. This provides a powerful economic argument for its use on hospital formularies.

Table 7: Cost-Effectiveness Comparison for HRS Treatment in the U.S. Hospital Setting

Treatment	Clinical Response Rate (HRS Reversal)	Total Cost per Patient (USD)	Cost per Complete Response (USD)	Source(s)
Terlipressin + Albumin	36.2%	$163,481	$451,605	47
Norepinephrine + Albumin	19.1%	$177,298	$930,571	47
Midodrine/Octreotide + Albumin	3.1%	$155,030	$4,942,123	47

Section 9: Conclusion and Future Perspectives

Terlipressin is a potent vasoactive agent with a well-defined mechanism of action that directly targets the pathophysiology of complications arising from severe portal hypertension. Its approval in the United States for hepatorenal syndrome with acute kidney injury marks a significant therapeutic milestone, providing the first-ever approved pharmacological treatment for a condition with extremely high mortality. Its long-standing use for acute variceal bleeding internationally further solidifies its role as a critical tool in the management of patients with advanced liver disease.

However, the efficacy of terlipressin is inextricably linked to a substantial and serious safety profile. The risk of life-threatening respiratory failure and ischemic events necessitates a highly disciplined approach to its use. The global regulatory consensus that has emerged—codified in the FDA's Boxed Warning and the EMA's safety recommendations—provides clear, data-driven guardrails for patient selection. Optimal outcomes with terlipressin can only be achieved through careful patient screening to exclude those at highest risk (e.g., SCr >5 mg/dL, ACLF Grade 3, active hypoxia or ischemia) and meticulous, continuous monitoring of respiratory status during therapy. The decision to use terlipressin, particularly in patients who are candidates for liver transplant, requires a nuanced and individualized assessment of the potential for short-term renal improvement against the risk of adverse events that could preclude life-saving surgery.

Several key questions remain and will shape the future use of terlipressin. Further research is needed to prospectively validate the safety and efficacy of continuous infusion regimens compared to traditional bolus dosing, a strategy that holds promise for mitigating adverse events. Its potential role in other critical care scenarios, such as norepinephrine-resistant septic shock—an indication for which current guidelines recommend against its use—warrants further investigation.[1] Finally, the development of biomarkers or clinical scoring systems to more accurately predict which patients are most likely to respond to terlipressin versus those who are most susceptible to its severe adverse effects would represent a major advance, allowing for more precise and personalized application of this powerful but challenging medication.

Appendix: Global Brand Names

Table 8: International Brand Names of Terlipressin

Brand Name	Country/Region	Manufacturer	Source(s)
Terlivaz	United States	Mallinckrodt	1
Glypressin	Australia, Belgium, Brazil, China, Czech Republic, Denmark, Egypt, Finland, Hong Kong, Hungary, Iceland, Ireland, Israel, Lithuania, Malaysia, Netherlands, Norway, Oman, Peru, Poland, Singapore, Slovenia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, UK, Vietnam	Ferring	49
Glypressine	France, Tunisia	Ferring	49
Glycylpressin	Germany, Tunisia	Ferring	49
Remestyp	Bulgaria, China, Czech Republic, Georgia, Poland, Slovakia	Ferring, Zentiva	49
Variquel	France, Malta, Netherlands, Spain, Sweden, UK	Alliance, Hospira, Pfizer, Sintetica	10
Haemopressin	France, Germany, Ireland, Netherlands, Taiwan	Alliance, Sintetica, Wulfing	49
Lucassin	Australia	Ikaria	49
Teri, Teriss, Terlinis	India	Health Biotech, Integra, Neiss	49
Terlipressin Acetate	Malta, UK	Cherubino, Ranbaxy	49
Glyverase	Mexico	Ferring	49
Glipressina	Italy	Ferring	49
Teripin	South Korea	Hanlim	49

Works cited

1. en.wikipedia.org, accessed August 5, 2025, https://en.wikipedia.org/wiki/Terlipressin
2. Terlivaz (terlipressin) FDA Approval History - Drugs.com, accessed August 5, 2025, https://www.drugs.com/history/terlivaz.html
3. Terlipressin | C52H74N16O15S2 | CID 72081 - PubChem, accessed August 5, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Terlipressin
4. Terlipressin: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed August 5, 2025, https://go.drugbank.com/drugs/DB02638
5. Terlipressin Acetate | CAS 14636-12-5 | SCBT, accessed August 5, 2025, https://www.scbt.com/p/terlipressin-acetate-14636-12-5
6. Terlipressin EP Reference Standard CAS 14636-12-5 Sigma Aldrich, accessed August 5, 2025, https://www.sigmaaldrich.com/US/en/product/sial/y0001897
7. Terlipressin - direct healthcare professional communication (DHPC) | European Medicines Agency (EMA), accessed August 5, 2025, https://www.ema.europa.eu/en/medicines/dhpc/terlipressin
8. Terlipressin acetate | 14636-12-5 - ChemicalBook, accessed August 5, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4266213.htm
9. Terlipressin (intravenous route) - Side effects & uses - Mayo Clinic, accessed August 5, 2025, https://www.mayoclinic.org/drugs-supplements/terlipressin-intravenous-route/description/drg-20539895
10. Terlipressin-containing medicinal products indicated in the treatment of hepatorenal syndrome - referral - EMA, accessed August 5, 2025, https://www.ema.europa.eu/en/medicines/human/referrals/terlipressin-containing-medicinal-products-indicated-treatment-hepatorenal-syndrome
11. Formulary Drug Reviews: Terlipressin - PMC - PubMed Central, accessed August 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10977064/
12. PUBLIC ASSESSMENT REPORT of the Medicines Evaluation Board in the Netherlands Terlipressine SUN 0.1 mg/ml, solution for injectio - Geneesmiddeleninformatiebank, accessed August 5, 2025, https://www.geneesmiddeleninformatiebank.nl/pars/h110384.pdf
13. FDA Approves Terlipressin for the Management of HRS-1 - Drug Topics, accessed August 5, 2025, https://www.drugtopics.com/view/fda-approves-terlipressin-for-the-management-of-hrs-1
14. Terlipressin Acetate; [14636-12-5], accessed August 5, 2025, https://www.peptide.com/product/terlipressin-acetate-14636-12-5/
15. Terlivaz (terlipressin) dosing, indications, interactions, adverse effects, and more, accessed August 5, 2025, https://reference.medscape.com/drug/terlivaz-terlipressin-4000107
16. Terlipressin (TERLIVAZ) in Hepatorenal Syndrome National Drug Monograph January 2023 | VA.gov, accessed August 5, 2025, https://www.va.gov/formularyadvisor/DOC_PDF/MON_Terlipressin_TERLIVAZ_in_Hepatorenal_Syndrome_Monograph_Jan_2023.pdf
17. Terlipressin Acetate Supplier USA | API Chemical CAS 14636-12-5 - Tecoland Corporation, accessed August 5, 2025, http://tecoland.com/terlipressin-acetate/
18. Terlipressin acetate | DrugBank Online, accessed August 5, 2025, https://go.drugbank.com/salts/DBSALT002332
19. About TERLIVAZ® | TERLIVAZ® (terlipressin) for injection, accessed August 5, 2025, https://www.terlivaz.com/about-terlivaz/
20. What is the role for terlipressin in hepatorenal syndrome?, accessed August 5, 2025, https://www.ccjm.org/content/90/11/664
21. What are current guideline recommendations for use of terlipressin in hepatorenal syndrome? | Drug Information Group | University of Illinois Chicago, accessed August 5, 2025, https://dig.pharmacy.uic.edu/faqs/2023-2/january-2023-faqs/what-are-current-guideline-recommendations-for-use-of-terlipressin-in-hepatorenal-syndrome/
22. Mallinckrodt Receives US FDA Approval for Terlivaz ® (terlipressin) for injection for the Treatment of Hepatorenal Syndrome (HRS), accessed August 5, 2025, https://www.mallinckrodt.com/about/news-and-media/news-detail/?id=29396
23. TERLIVAZ® (terlipressin) for injection | Official HCP Site, accessed August 5, 2025, https://www.terlivaz.com/
24. Comparative efficacy of terlipressin and norepinephrine for ..., accessed August 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10824429/
25. Use of Terlipressin in AKI Associated with Hepatorenal Syndrome: CON - PMC, accessed August 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11219101/
26. Mallinckrodt Announces Resubmission of Terlipressin to the FDA for the Treatment of Hepatorenal Syndrome - Investor Relations, accessed August 5, 2025, https://mallinckrodt.gcs-web.com/news-releases/news-release-details/mallinckrodt-announces-resubmission-terlipressin-fda-treatment/
27. Reference ID: 5045489 - accessdata.fda.gov, accessed August 5, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022231s000lbl.pdf
28. The pharmacodynamic effect of terlipressin versus high-dose ..., accessed August 5, 2025, https://atm.amegroups.org/article/view/66641/html
29. Terlipressin vs. octreotide in bleeding esophageal varices as an adjuvant therapy with endoscopic band ligation: a randomized double-blind placebo-controlled trial - PubMed, accessed August 5, 2025, https://pubmed.ncbi.nlm.nih.gov/19223890/
30. Comparison of drugs facilitating endoscopy for patients with acute variceal bleeding: a systematic review and network meta-analysis - Annals of Translational Medicine, accessed August 5, 2025, https://atm.amegroups.org/article/view/33261/html
31. Study Details | Comparison of Terlipressin, Somatostatin, and Octreotide for Control of Variceal Bleeding | ClinicalTrials.gov, accessed August 5, 2025, https://clinicaltrials.gov/study/NCT00966355
32. What is the dose of terlipressin for acute variceal bleeding? - Dr.Oracle, accessed August 5, 2025, https://www.droracle.ai/articles/91363/dose-of-terlipressin-on-variceal-bleeding
33. Management of Suspected Variceal Bleeding - GGC Medicines, accessed August 5, 2025, https://handbook.ggcmedicines.org.uk/guidelines/gastrointestinal-system/management-of-suspected-variceal-bleeding/
34. What is the recommended dosage of terlipressin for managing bleeding esophageal varices? - Dr.Oracle AI, accessed August 5, 2025, https://www.droracle.ai/articles/192077/terlipressin-dosage-for-esophageal-varices-bleed
35. New recommendations for terlipressin-containing medicines in the treatment of hepatorenal syndrome - AIFA, accessed August 5, 2025, https://www.aifa.gov.it/en/-/nuove-raccomandazioni-medicinali-a-base-di-terlipressina-nel-trattamento-della-sindrome-epatorenale
36. Terlipressin • LITFL • CCC Pharmacology, accessed August 5, 2025, https://litfl.com/terlipressin/
37. ADR that result in revision of patient information - 2022-10-03 (1), accessed August 5, 2025, https://www.drugoffice.gov.hk/eps/news/showNews/European+Union%3A+New+recommendations+for+terlipressin-containing+medicines+in+the+treatment+of+hepatorenal+syndrome/healthcare_providers/2022-10-03/en/48026.html
38. Dosing & Administration | TERLIVAZ® (terlipressin) for injection, accessed August 5, 2025, https://www.terlivaz.com/dosing-and-administration/
39. Review of terlipressin medicines started - AIFA, accessed August 5, 2025, https://www.aifa.gov.it/documents/20142/1621464/2022.01.14_com-EMA_Avviata_revisione_terlipressina_EN.pdf
40. Terlipressin - EMA, accessed August 5, 2025, https://www.ema.europa.eu/en/documents/referral/terlipressin-containing-medicinal-products-article-31-referral-annex-iii_en.pdf
41. TERLIPRESSIN EVER PHARMA 1 mg/5 mL solution for injection - NEW ZEALAND DATA SHEET, accessed August 5, 2025, https://www.medsafe.govt.nz/profs/datasheet/t/terlipressinEverPharmainj.pdf
42. Use of Terlipressin in AKI Associated with Hepatorenal Syndrome: COMMENTARY - PMC, accessed August 5, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11219104/
43. Comparative efficacy of terlipressin and norepinephrine for treatment of hepatorenal syndrome-acute kidney injury: A systematic review and meta-analysis | PLOS One - Research journals, accessed August 5, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0296690
44. Terlipressin versus Norepinephrine in the Treatment of Hepatorenal Syndrome: A Systematic Review and Meta-Analysis | PLOS One - Research journals, accessed August 5, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107466
45. Terlipressin Is Superior to Noradrenaline in the Management of Acute Kidney Injury in Acute on Chronic Liver Failure - PubMed, accessed August 5, 2025, https://pubmed.ncbi.nlm.nih.gov/30076614/
46. Which Vasoactive Medications Are Most Effective for Hepatorenal Syndrome?, accessed August 5, 2025, https://www.jwatch.org/na55305/2022/10/06/which-vasoactive-medications-are-most-effective
47. Cost-effectiveness of terlipressin for hepatorenal syndrome: the ..., accessed August 5, 2025, https://pubmed.ncbi.nlm.nih.gov/37729445/
48. Cost-effectiveness of terlipressin for hepatorenal syndrome - OPEN Health, accessed August 5, 2025, https://www.openhealthgroup.com/publication-library/cost-effectiveness-of-terlipressin-for-hepatorenal-syndrome-the-united-states-hospital-perspective/
49. Terlipressin (International database) - Drugs.com, accessed August 5, 2025, https://www.drugs.com/international/terlipressin.html