Terlipressin may cause serious or fatal respiratory failure. Patients with volume overload or with acute-on-chronic liver failure (ACLF) Grade 3 are at increased risk. Assess oxygenation saturation (eg, SpO2) before initiating terlipressin.
Do not initiate terlipressin in patients experiencing hypoxia (eg, SpO2 <90%) until oxygenation levels improve. Monitor patients for hypoxia using continuous pulse oximetry during treatment and discontinue terlipressin if SpO2 decreases below 90%.
Hepatorenal syndrome: Note: Patients with SCr >5 mg/dL at the time of treatment initiation are unlikely to experience benefit. Concurrent use of albumin was utilized in clinical trials.
IV: Initial: 0.85 mg every 6 hours for 3 days. Beginning on day 4, adjust dose based on SCr as follows:
If SCr has decreased by ≥30% from baseline: Continue 0.85 mg every 6 hours until 24 hours after patient achieves 2 consecutive creatinine values (at least 2 hours apart) of ≤1.5 mg/dL or for a maximum of 14 days.
If SCr has decreased by <30% from baseline: Increase to 1.7 mg every 6 hours; continue until 24 hours after patient achieves 2 consecutive creatinine values (at least 2 hours apart) of ≤1.5 mg/dL or for a maximum of 14 days.
If SCr ≥ baseline: Discontinue terlipressin.
Mild to severe impairment: Note: Patients with SCr >5 mg/dL at the time of treatment initiation are unlikely to experience benefit.
Initial: No dosage adjustment necessary (<1% eliminated in the urine); subsequent dose adjustments should be determined based on SCr response beginning on day 4 of therapy (see adult dosing for specific recommendations).
Mild to severe impairment: No dosage adjustment necessary.
Refer to adult dosing.
Fluid overload: In conjunction with reducing or discontinuing the administration of albumin and/or other fluids and judicious use of diuretics, temporarily interrupt, reduce, or discontinue terlipressin until patient volume status improves.
Ischemic signs or symptoms: Discontinue terlipressin in patients with signs of ischemia (eg, angina, ECG changes, abdominal pain, peripheral cyanosis, or extremity pain).
Respiratory effects: Discontinue terlipressin in patients who develop hypoxia or increase in respiratory symptoms.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous, as acetate [preservative free]:
Terlivaz: 0.85 mg (1 ea)
No
IV: Administer as an IV bolus slowly over 2 minutes through a peripheral or central line. Flush the line after administration.
Hepatorenal syndrome: To improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.
Note: The American Association for the Study of Liver Diseases guidance for the diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome, the American College of Gastroenterology clinical guidelines for acute-on-chronic liver failure and the European Association for the Study of the Liver guidelines for the management of decompensated cirrhosis recommend terlipressin (in combination with albumin) as a first-line treatment option (AASLD [Biggins 2021]; ACG [Bajaj 2022]; EASL [Angeli 2018]).
Hyponatremia has been reported with terlipressin administration; can be severe, inducing neurological manifestations (eg, change in mental status, cognitive deficits, delirium, encephalopathy, personality changes, seizures) (Ref). Onset of hyponatremia may be preceded by a substantial fluid retention (Ref). Serum sodium levels typically recover rapidly after discontinuation of terlipressin (Ref).
Mechanism: Dose-related; likely due to stimulation of V1 receptors of the smooth muscles in the splanchnic area (improving circulatory volume and urine volume) and V2 receptors in the renal collecting ducts (resulting in antidiuretic activity by reducing solute-free water clearance and increasing water reabsorption causing a dilution hyponatremia) (Ref).
Onset: Rapid; onset has been reported within 2 to 5 days (Ref).
Risk factors:
• Decreased model for end-stage liver disease (MELD) scores, preserved hepatic function (Ref)
• Baseline serum sodium levels (Ref)
• Younger age (Ref)
Severe and life-threatening ischemic events, including cardiac ischemia (eg, acute myocardial infarction), cerebrovascular ischemia, mesenteric ischemia (eg, intestinal necrosis), and peripheral ischemia (eg, peripheral cyanosis, skin necrosis, peripheral gangrene, skin discoloration) have been reported with terlipressin (Ref).
Mechanism: Dose-related; activated V receptors (especially V1 receptors) produce vasoconstrictive effects on cardiac, splanchnic, and peripheral circulation (Ref).
Onset: Varied; can occur within 1 to 11 days of terlipressin administration (Ref).
Risk factors:
• History of severe cardiovascular, cerebrovascular, and/or ischemic disease
• Hypovolemia (Ref)
• Concomitant pressor drugs (Ref)
• Continuous infusion administration (Ref)
• Obesity (Ref)
• Venous insufficiency (Ref)
• Spontaneous bacterial peritonitis (Ref)
• Non-alcoholic fatty liver disease-related cirrhosis (potential risk factor) (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Gastrointestinal: Abdominal pain (20%), diarrhea (13%), nausea (16%)
Respiratory: Dyspnea (13%), respiratory failure (16%; severe: 14%) (table 1)
|
Drug (Terlipressin) |
Placebo |
Dose |
Number of Patients (Terlipressin) |
Number of Patients (Placebo) |
|---|---|---|---|---|
|
16% |
7% |
Average daily dose of 3.1 mg (range 0.8 to 5.8 mg) |
200 |
99 |
|
Severe: 14% |
5% |
Average daily dose of 3.1 mg (range 0.8 to 5.8 mg) |
200 |
99 |
1% to 10%:
Cardiovascular: Bradycardia (5%), ischemia (5%; including cyanosis, mesenteric ischemia, peripheral cyanosis [Chiang 2019], peripheral gangrene [Lee 2013], peripheral ischemia [Elzouki 2010], skin discoloration, and skin necrosis [Nistal 2021]) (table 2)
|
Drug (Terlipressin) |
Placebo |
Dose |
Number of Patients (Terlipressin) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
5% |
0% |
Average daily dose of 3.1 mg (range 0.8 to 5.8 mg) |
200 |
99 |
Described as ischemia-related events including skin discoloration, cyanosis, ischemia, and intestinal ischemia. |
Endocrine & metabolic: Hypervolemia (9%)
Infection: Sepsis (6%)
Respiratory: Pleural effusion (6%)
Postmarketing:
Cardiovascular: Acute myocardial infarction (Carmo 2016, Lee 2004), cardiogenic shock (Elzouki 2010), left ventricular dysfunction (including left ventricular failure, left ventricular posterior wall hypokinesia, and takotsubo cardiomyopathy) (DiMicoli 2011, Ghatak 2014), prolonged QT interval on ECG (including torsades de pointes) (Sidhu 2013), supraventricular tachycardia (Elzouki 2010), ventricular dysfunction (Elzouki 2010)
Dermatologic: Gangrene of skin and/or subcutaneous tissues (Elzouki 2010, Lee 2013), skin necrosis (Kulkarni 2020, Nistal 2021)
Endocrine & metabolic: Hyponatremia (Meng 2019, Sima 2016)
Gastrointestinal: Intestinal necrosis (Kim 2013)
Nervous system: Headache
Neuromuscular & skeletal: Rhabdomyolysis (Zimmer 2010)
Patients with ongoing coronary, peripheral or mesenteric ischemia; hypoxia or worsening respiratory symptoms.
Concerns related to adverse effects:
• Ischemic events: Ischemic events, including cardiac, cerebrovascular, peripheral, and mesenteric ischemia, may occur.
Disease-related concerns:
• Acute-on-chronic liver failure: Avoid use in patients with acute-on-chronic liver failure grade 3, as these patients are at significantly increased risk of respiratory failure.
• Cardiovascular disease: Avoid use in patients with a history of severe cardiovascular conditions, cerebrovascular disease, and ischemic disease, as terlipressin may cause ischemic events.
• Hypervolemia: Patients with fluid overload are at increased risk of respiratory failure. Manage intravascular volume overload by interrupting or reducing the administration of albumin/other fluids and/or the judicious use of diuretic therapy.
Special populations:
• Liver transplant candidates: Terlipressin-related adverse reactions (respiratory failure, ischemia) may make a patient ineligible for liver transplantation, if listed. For patients with high prioritization for liver transplantation (eg, MELD ≥35), evaluate the benefits versus the risks of terlipressin therapy.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy
Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modification
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination
Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Terlipressin causes uterine contractions and endometrial ischemia. Based on the mechanism of action and data from animal reproduction studies, in utero exposure to terlipressin may cause fetal harm.
It is not known if terlipressin is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Serum creatinine (baseline and periodically during therapy); oxygen saturation (baseline and during therapy via continuous pulse oximetry and clinical assessments); Acute-on-Chronic Liver Failure Grade and volume status (baseline and periodically during treatment); signs and symptoms of fluid overload or ischemia.
Terlipressin, a synthetic vasopressin analogue, has intrinsic activity; however, a majority of the activity results from conversion to lysine-vasopressin via slow enzymatic cleavage, producing an extended duration of systemic vasoconstriction. Reduces portal pressure and blood flow into portal vessels, increasing effective arterial blood volume and mean arterial pressure, thereby increasing blood flow to the kidneys.
Onset of action: BP and mean arterial pressure increased and heart rate decreased within 5 minutes.
Duration: ≥6 hours.
Distribution: Vd: Terlipressin: 6.3 L; lysine-vasopressin: 1,370 L.
Metabolism: Terlipressin is cleaved to lysine-vasopressin (active metabolite) by various tissue peptidases, which is then metabolized by tissue peptidase-mediated routes.
Half-life elimination: Terminal: Terlipressin: 0.9 hours; lysine-vasopressin: 3 hours.
Time to peak: Maximal change in BP and heart rate:1.2 to 2 hours post dose.
Excretion: Urine (terlipressin: <1%; lysine-vasopressin: <0.1%).
Solution (reconstituted) (Terlivaz Intravenous)
0.85 mg (per each): $1,140.00
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