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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
LIVMARLI (NDA-214662)
(MARALIXIBAT CHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
07/24/2024 (SUPPL-10)
5 Warnings and Precautions
5.4 Risk of Propylene Glycol Toxicity (Pediatric Patients Less Than 5 Years of Age)Newly added subsection:
LIVMARLI contains propylene glycol. Patients less than 5 years of age are at highest risk for propylene glycol toxicity, and a safe level for propylene glycol exposure with repeated administration has not been established for pediatric patients less than 5 years of age. When LIVMARLI is administered at the dose (380 mcg/kg once daily) for treatment of cholestatic pruritus in patients with ALGS, the exposure to propylene glycol will be 14.6 mg/kg/day. When LIVMARLI is administered at the dose (570 mcg/kg twice daily) for treatment of cholestatic pruritus in patients with PFIC, the exposure to propylene glycol will be 21.9 mg/kg/day. The total daily intake of propylene glycol from all sources should be considered for managing the risk of propylene glycol toxicity.
Monitor patients for signs of potential propylene glycol toxicity, including hemolysis, hyperosmolarity with anion gap metabolic acidosis, acute kidney injury, and CNS toxicity. Discontinue LIVMARLI if propylene glycol toxicity is suspected [see Overdosage (10)].
8 Use in Specific Populations
8.4 Peditric Use ALGSAdditions and revisions underlined:
PFIC
The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in PFIC have been established in pediatric patients aged 12 months of age and older. Use of LIVMARLI in this population is supported by evidence from Trial 2 in patients 1 to <18 years of age that included 26 weeks of placebo-controlled safety and efficacy data [see Adverse Reactions (6) and Clinical Studies (14.2)].
The 19 mg/mL formulation of LIVMARLI should be used in patients with PFIC in order to minimize exposure to excipients, including propylene glycol. Patients less than 5 years of age are at highest risk for propylene glycol toxicity. The total daily intake of propylene glycol from all sources should be considered for managing the risk of propylene glycol toxicity [see Warnings and Precautions (5.4)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient InformationAdditions and revisions underlined:
What is LIVMARLI?
LIVMARLI is a prescription medicine used to treat:
cholestatic pruritus (itch) in patients 3 months of age and older with Alagille syndrome (ALGS).
cholestatic pruritus (itch) in patients 12 months of age and older with progressive familial intrahepatic cholestasis (PFIC).
. . .
It is not known if LIVMARLI is safe and effective in children with PFIC who are under 12 months of age.
LIVMARLI comes in 2 different strengths:
LIVMARLI 9.5 mg/mL for use in ALGS
LIVMARLI 19 mg/mL for use in PFIC
Tell your healthcare provider if you have signs or symptoms of bleeding or any fractures.
03/13/2024 (SUPPL-5)
4 Contraindications
Additions and/or
revisions underlined:
LIVMARLI is contraindicated in patients with prior or active hepatic
decompensation events (e.g., variceal hemorrhage, ascites,
hepatic encephalopathy) [see Warnings and
Precautions (5.1)].
5 Warnings and Precautions
5.1 Hepatotoxicity
Subsection title revised
Additions and/or revisions underlined:
LIVMARLI treatment is associated with a potential for drug-induced liver injury.
In the PFIC trial, treatment-emergent hepatic decompensation events and elevations of liver tests or worsening of liver tests occurred. Two patients experienced drug-induced liver injury (DILI) attributable to LIVMARLI. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these four patients, one patient required liver transplant and another patient died.
In the ALGS trial, treatment-emergent elevations of liver tests or worsening of liver tests occurred. Most abnormalities included elevations in ALT, AST, and/or TB/DB. One patient whose TB was elevated at baseline discontinued LIVMARLI after 28 weeks due to increased TB above baseline. Four patients had ALT increases that led to dose modification (n=1), dose interruption (n=2), or permanent discontinuation (n=2) of LIVMARLI during the long-term, open-label extension period [see Adverse Reactions (6.1)]. Obtain baseline liver tests because some ALGS and PFIC patients have abnormal liver tests at baseline. Monitor patients frequently for the first 6 to 8 months after starting therapy and as clinically indicated thereafter during treatment with LIVMARLI. Monitor for elevations in liver tests, for the development of liver-related adverse reactions, and for physical signs of hepatic decompensation. If liver test abnormalities or signs of clinical hepatitis occur in the absence of other causes, consider dose reduction or treatment interruption.
Permanently discontinue LIVMARLI if a patient experiences the following:
persistent or recurrent liver test abnormalities, or
upon rechallenge, signs and symptoms consistent with clinical hepatitis, or
a hepatic decompensation event.
The safety and effectiveness of LIVMARLI have not been established in patients with decompensated cirrhosis. Monitor patients with compensated cirrhosis frequently and discontinue LIVMARLI if hepatic decompensation occurs. LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events [see Contraindications (4)].
5.2 Gastrointestinal Adverse Reactions
Additions and/or revisions underlined:
Diarrhea and abdominal pain were reported as the most common adverse reactions in patients treated with LIVMARLI [see Adverse Reactions (6.1)].
Consider reducing the dosage or interrupting LIVMARLI treatment if a patient experiences persistent diarrhea or abdominal pain, or has diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever. Consider stopping LIVMARLI treatment if diarrhea or abdominal pain persists and no alternate etiology is identified. Monitor for dehydration due to diarrhea and treat promptly.
LIVMARLI was not evaluated in PFIC patients with chronic diarrhea requiring intravenous fluids.
When diarrhea or abdominal pain resolves, restart LIVMARLI at the last tolerated dose and increase the dose as tolerated. Consider stopping LIVMARLI treatment if they recur upon re-challenge with LIVMARLI.
5.3 Fat Soluble Vitamin (FSV) Deficiency
Additions and/or revisions underlined:
LIVMARLI may adversely affect absorption of fat-soluble vitamins (FSV). FSV include vitamins A, D, E, and K (measured using INR levels). ALGS and PFIC patients can have FSV deficiency at baseline and are frequently supplemented with FSV.
In ALGS patients in Trial 1, treatment-emergent FSV deficiency was reported in 3 (10%) patients
during 48 weeks of treatment.
In PFIC patients in Trial 2, treatment-emergent FSV deficiency (assessed biochemically) was reported in 13 (28%) of LIVMARLI-treated patients versus 16 (35%) of placebo-treated patients during 26 weeks of treatment.
Bone Fracture
Treatment-emergent bone fracture events have been observed more frequently with LIVMARLI- treated patients compared to placebo-treated patients [see Adverse Reactions (6.1)]. If fracture occurs, consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.
Bleeding
If bleeding occurs, interrupt treatment with LIVMARLI. LIVMARLI can be restarted if FSV deficiency is corrected and bleeding has resolved.
Obtain serum FSV levels prior to initiation of LIVMARLI and monitor the levels periodically during treatment, along with any clinical manifestations of FSV deficiency. Supplement with FSV if FSV deficiency is diagnosed. Consider discontinuing LIVMARLI if FSV deficiency persists or worsens despite adequate FSV supplementation.
If complications of FSV deficiency occur, such as fracture or bleeding, consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.
6 Adverse Reactions
Addition of the following to the bulleted line listing:
The following clinically significant adverse reactions are described elsewhere in labeling:
Hepatotoxicity [see Warnings and Precautions (5.1)]
Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2)]
Fat Soluble Vitamin (FSV) Deficiency [see Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Extensive changes; please refer to label for complete information
6.2 Postmarketing Experience
Newly added subsection:
The following adverse reactions have been identified during post approval use of LIVMARLI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: hematemesis, liver transplant, post-endoscopy hemorrhage, post-liver biopsy hemorrhage
General disorders and administration site conditions: drug ineffective Injury, poisoning and procedural complications: off label use Investigations: gamma-glutamyltransferase increased
Nervous system disorders: intracranial hemorrhage
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk Summary
Maternal use at the recommended clinical dose of LIVMARLI is not expected to result in measurable fetal exposure because systemic absorption following oral administration is low [see Clinical Pharmacology (12.3)]. Maralixibat may inhibit the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3) and Clinical Considerations]. In animal reproduction studies, no developmental effects were observed (see Data).
The estimated background risk of major birth defects for ALGS is higher than the general population because ALGS is an autosomal dominant condition. The background risk of miscarriage for ALGS is unknown. The background risk of birth defects and miscarriage for PFIC is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
…
8.2 Lactation
Additions and/or revisions underlined:
Risk Summary
LIVMARLI has low absorption following oral administration, and breastfeeding is not expected to result in exposure of the infant to LIVMARLI at the recommended dose [see Clinical Pharmacology (12.3)]. There are no data on the presence of LIVMARLI in human milk, the effects on the breastfed infant, or the effects on milk production. Patients with ALGS or PFIC can have FSV deficiency as part of their disease. Maralixibat may reduce absorption of fat-soluble vitamins [see Warnings and Precautions (5.3)]. Monitor FSV levels and supplement FSV intake, if FSV deficiency is observed during lactation. The developmental and health benefits of breastfeeding should be considered along with the mother’s need for LIVMARLI and any potential adverse effects on the breastfed child from LIVMARLI or from the underlying maternal condition.
8.4 Pediatric Use
Additions and/or revisions underlined:
ALGS
The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in Alagille syndrome have been established in pediatric patients aged 3 months of age and older. Use of LIVMARLI in this population is supported by evidence from a study of patients 1 to 15 years of age (N=31) that included 18 weeks of open-label treatment followed by a 4 week placebo-controlled randomized withdrawal period and a subsequent 26-week open-label treatment period. Additional safety information was obtained from four studies in patients up to 21 years of age (N=55) [see Adverse Reactions (6) and Clinical Studies (14.1)]. Use of LIVMARLI in patients 3 to <12 months of age is supported by an open-label, multicenter study of LIVMARLI which showed a similar safety, tolerability and pharmacokinetic profile to patients with ALGS >12 months of age.
The safety and effectiveness of LIVMARLI have not been established in patients with ALGS less than 3 months of age.
PFIC
The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in PFIC have been established in pediatric patients aged 5 years of age and older. Use of LIVMARLI in this population is supported by evidence from Trial 2 in patients 1 to <18 years of age that included 26 weeks of placebo-controlled safety and efficacy data [see Adverse Reactions (6) and Clinical Studies (14.2)].
The safety and effectiveness of LIVMARLI have not been established in patients with PFIC younger than 12 months of age.
8.5 Geriatric Use
Additions and/or
revisions underlined:
The safety
and effectiveness of LIVMARLI for the treatment of pruritus in ALGS or
PFIC in adult patients, 65 years of age and
older, have not been established.
8.6 Hepatic Impairment
Additions and/or
revisions underlined:
Clinical
studies of LIVMARLI included ALGS or PFIC patients with impaired hepatic
function at baseline. The efficacy and safety in ALGS or PFIC patients
with clinically significant portal hypertension and in patients
with decompensated cirrhosis
have not been established. LIVMARLI is contraindicated in patients with prior or active hepatic
decompensation events [see Dosage and
Administration (2.5), Contraindications (4), Warnings and Precautions (5.1), and Clinical Studies (14)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or
revisions underlined:
Advise the patient or their caregiver(s) to read the FDA-approved patient
labeling (Patient Information and Instructions for Use).
Administration Instructions
Advise patients or their caregivers(s) to:
Take LIVMARLI 30 minutes prior to a meal once or twice daily as prescribed using a calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dispenser) provided by the pharmacist to measure and deliver the prescribed dose accurately [see Dosage and Administration (2.1, 2.2 2.4)].
Take LIVMARLI at least 4 hours before or 4 hours after taking a bile acid binding resin (e.g., cholestyramine, colesevelam, or colestipol) [see Drug Interactions (7.1)].
Store the opened bottle below 30?C (86?F). Discard any unused LIVMARLI 100 days after opening the bottle [see How Supplied/Storage and Handling (16)].
Hepatotoxicity
Advise patients or their caregiver(s) that liver tests should be obtained before starting LIVMARLI and periodically during LIVMARLI therapy. Inform patients or their caregiver(s) of the risk of hepatotoxicity that could be fatal and that they will need to undergo monitoring for liver injury. Instruct patients or their caregiver(s) to immediately report any signs or symptoms of severe liver injury to their healthcare provider [see Warnings and Precautions (5.1)].
Gastrointestinal Adverse Reactions
Advise patients or their caregiver(s) to notify their healthcare provider if they experience a new onset or worsening of gastrointestinal symptoms (abdominal pain, vomiting, bloody stool, and diarrhea) [see Warnings and Precautions (5.2)].
Fat Soluble Vitamin (FSV) Deficiency
Advise patients or their caregiver(s) that INR (for vitamin K) and serum levels of vitamins A, D, E will be obtained before starting treatment and periodically during treatment to assess for FSV deficiency [see Warnings and Precautions (5.3)]. Inform patients or their caregiver(s) that they may bleed more easily, may bleed longer, or have a bone fracture. Advise patients or their caregiver(s) to call their healthcare provider for any signs or symptoms of bleeding or report any fractures.
Additions
and/or revisions underlined:
What is LIVMARLI?
LIVMARLI is a prescription medicine used to treat:
cholestatic pruritus (itch) in patients 3 months of age and older with Alagille syndrome (ALGS).
cholestatic pruritus (itch) in patients 5 years of age and older with progressive familial intrahepatic cholestasis (PFIC).
LIVMARLI is not for use in PFIC type 2 patients who have a severe defect in the bile salt export pump (BSEP) protein.
It is not known if LIVMARLI is safe and effective in children with ALGS who are under 3 months of age.
It is not known if LIVMARLI is safe and effective in children with PFIC who are under 5 years of age.
It is not known if LIVMARLI is safe and effective in adults 65 years of age and older.
…
How should you take LIVMARLI?
Read the Instructions for Use that comes with LIVMARLI for information about the right way to prepare and take LIVMARLI.
Before you take LIVMARLI for the first time, talk to your healthcare provider or pharmacist about how to measure the prescribed dose.
Take LIVMARLI exactly as your healthcare provider tells you to.
Your healthcare provider may start you on a low dose of LIVMARLI and then increase the dose, especially if you have not taken LIVMARLI.
Do not change your dose of LIVMARLI unless your healthcare provider tells you to.
LIVMARLI is taken by mouth, 1 or 2 times each day (if 2 times per day, take in the morning and evening), 30 minutes before a meal.
If you miss a dose of LIVMARLI and you take LIVMARLI 1-time a day:
If it is 12 hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.
If it is more than 12 hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time.
If you miss a dose of LIVMARLI and you take LIVMARLI 2-times a day:
If it is 6 hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.
If it is more than 6 hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time.
If you take a medicine that lowers cholesterol by binding bile acids, such as cholestyramine, colesevelam, or colestipol, take it at least 4 hours before or 4 hours after you take LIVMARLI. Ask your healthcare provider if you are not sure if you take these medicines.
If you take too much LIVMARLI, call your healthcare provider or go to the nearest emergency room right away.
Throw away any remaining LIVMARLI 100 days after first opening the bottle.
…
What are the possible side effects of LIVMARLI?
LIVMARLI can cause serious side effects, including:Liver injury. Changes in certain liver tests are common in patients with ALGS and in patients with PFIC but may worsen during treatment with LIVMARLI. These changes may be a sign of liver injury and can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment with LIVMARLI to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including:
nausea or vomiting
your skin or the white part of your eye turns yellow
dark or brown urine
pain on the right side of your stomach (abdomen)
fullness, bloating, or fluid in your stomach area (ascites)
loss of appetite
bleeding or bruising more easily than normal, including vomiting blood
Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain during treatment. Diarrhea can also cause the loss of too much body fluid (severe dehydration). Your healthcare provider should check your stool for blood and monitor you for too much body fluid loss.
Tell your healthcare provider right away if you have any new or worsening signs or symptoms of stomach and intestinal problems including:
diarrhea
more frequent bowel movements than usual
stools that are black, tarry, sticky, or have blood or mucous
severe stomach-area pain or tenderness
Tell your healthcare provider if you have any signs and symptoms of a loss of too much body fluid including:
vomiting
urinating less often than usual
dizziness
diarrhea
headache
A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat. FSV deficiency is common in patients with ALGS and in patients with PFIC but may worsen during treatment with LIVMARLI. Your healthcare provider should do blood tests before starting and during treatment with LIVMARLI.
Other common side effects of FSV deficiency reported during treatment with LIVMARLI were bone fractures and bleeding.
Your healthcare provider may change your dose, or temporarily or permanently stop treatment with LIVMARLI if you have certain side effects.
These are not all of the possible side effects of LIVMARLI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088.
…
03/13/2024 (SUPPL-8)
4 Contraindications
Additions and/or
revisions underlined:
LIVMARLI is contraindicated in patients with prior or active hepatic
decompensation events (e.g., variceal hemorrhage, ascites,
hepatic encephalopathy) [see Warnings and
Precautions (5.1)].
5 Warnings and Precautions
5.1 Hepatotoxicity
Subsection title revised
Additions and/or revisions underlined:
LIVMARLI treatment is associated with a potential for drug-induced liver injury.
In the PFIC trial, treatment-emergent hepatic decompensation events and elevations of liver tests or worsening of liver tests occurred. Two patients experienced drug-induced liver injury (DILI) attributable to LIVMARLI. Two additional patients experienced DILI in the open-label extension portion of the trial. Of these four patients, one patient required liver transplant and another patient died.
In the ALGS trial, treatment-emergent elevations of liver tests or worsening of liver tests occurred. Most abnormalities included elevations in ALT, AST, and/or TB/DB. One patient whose TB was elevated at baseline discontinued LIVMARLI after 28 weeks due to increased TB above baseline. Four patients had ALT increases that led to dose modification (n=1), dose interruption (n=2), or permanent discontinuation (n=2) of LIVMARLI during the long-term, open-label extension period [see Adverse Reactions (6.1)]. Obtain baseline liver tests because some ALGS and PFIC patients have abnormal liver tests at baseline. Monitor patients frequently for the first 6 to 8 months after starting therapy and as clinically indicated thereafter during treatment with LIVMARLI. Monitor for elevations in liver tests, for the development of liver-related adverse reactions, and for physical signs of hepatic decompensation. If liver test abnormalities or signs of clinical hepatitis occur in the absence of other causes, consider dose reduction or treatment interruption.
Permanently discontinue LIVMARLI if a patient experiences the following:
persistent or recurrent liver test abnormalities, or
upon rechallenge, signs and symptoms consistent with clinical hepatitis, or
a hepatic decompensation event.
The safety and effectiveness of LIVMARLI have not been established in patients with decompensated cirrhosis. Monitor patients with compensated cirrhosis frequently and discontinue LIVMARLI if hepatic decompensation occurs. LIVMARLI is contraindicated in patients with prior or active hepatic decompensation events [see Contraindications (4)].
5.2 Gastrointestinal Adverse Reactions
Additions and/or revisions underlined:
Diarrhea and abdominal pain were reported as the most common adverse reactions in patients treated with LIVMARLI [see Adverse Reactions (6.1)].
Consider reducing the dosage or interrupting LIVMARLI treatment if a patient experiences persistent diarrhea or abdominal pain, or has diarrhea with bloody stool, vomiting, dehydration requiring treatment, or fever. Consider stopping LIVMARLI treatment if diarrhea or abdominal pain persists and no alternate etiology is identified. Monitor for dehydration due to diarrhea and treat promptly.
LIVMARLI was not evaluated in PFIC patients with chronic diarrhea requiring intravenous fluids.
When diarrhea or abdominal pain resolves, restart LIVMARLI at the last tolerated dose and increase the dose as tolerated. Consider stopping LIVMARLI treatment if they recur upon re-challenge with LIVMARLI.
5.3 Fat Soluble Vitamin (FSV) Deficiency
Additions and/or revisions underlined:
LIVMARLI may adversely affect absorption of fat-soluble vitamins (FSV). FSV include vitamins A, D, E, and K (measured using INR levels). ALGS and PFIC patients can have FSV deficiency at baseline and are frequently supplemented with FSV.
In ALGS patients in Trial 1, treatment-emergent FSV deficiency was reported in 3 (10%) patients
during 48 weeks of treatment.
In PFIC patients in Trial 2, treatment-emergent FSV deficiency (assessed biochemically) was reported in 13 (28%) of LIVMARLI-treated patients versus 16 (35%) of placebo-treated patients during 26 weeks of treatment.
Bone Fracture
Treatment-emergent bone fracture events have been observed more frequently with LIVMARLI- treated patients compared to placebo-treated patients [see Adverse Reactions (6.1)]. If fracture occurs, consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.
Bleeding
If bleeding occurs, interrupt treatment with LIVMARLI. LIVMARLI can be restarted if FSV deficiency is corrected and bleeding has resolved.
Obtain serum FSV levels prior to initiation of LIVMARLI and monitor the levels periodically during treatment, along with any clinical manifestations of FSV deficiency. Supplement with FSV if FSV deficiency is diagnosed. Consider discontinuing LIVMARLI if FSV deficiency persists or worsens despite adequate FSV supplementation.
If complications of FSV deficiency occur, such as fracture or bleeding, consider interrupting LIVMARLI treatment and supplement with FSV. LIVMARLI can be restarted once FSV deficiency is corrected and maintained at corrected levels.
6 Adverse Reactions
Addition of the following to the bulleted line listing:
The following clinically significant adverse reactions are described elsewhere in labeling:
Hepatotoxicity [see Warnings and Precautions (5.1)]
Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2)]
Fat Soluble Vitamin (FSV) Deficiency [see Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Extensive changes; please refer to label for complete information
6.2 Postmarketing Experience
Newly added subsection:
The following adverse reactions have been identified during post approval use of LIVMARLI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: hematemesis, liver transplant, post-endoscopy hemorrhage, post-liver biopsy hemorrhage
General disorders and administration site conditions: drug ineffective Injury, poisoning and procedural complications: off label use Investigations: gamma-glutamyltransferase increased
Nervous system disorders: intracranial hemorrhage
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk Summary
Maternal use at the recommended clinical dose of LIVMARLI is not expected to result in measurable fetal exposure because systemic absorption following oral administration is low [see Clinical Pharmacology (12.3)]. Maralixibat may inhibit the absorption of fat-soluble vitamins [see Warnings and Precautions (5.3) and Clinical Considerations]. In animal reproduction studies, no developmental effects were observed (see Data).
The estimated background risk of major birth defects for ALGS is higher than the general population because ALGS is an autosomal dominant condition. The background risk of miscarriage for ALGS is unknown. The background risk of birth defects and miscarriage for PFIC is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
…
8.2 Lactation
Additions and/or revisions underlined:
Risk Summary
LIVMARLI has low absorption following oral administration, and breastfeeding is not expected to result in exposure of the infant to LIVMARLI at the recommended dose [see Clinical Pharmacology (12.3)]. There are no data on the presence of LIVMARLI in human milk, the effects on the breastfed infant, or the effects on milk production. Patients with ALGS or PFIC can have FSV deficiency as part of their disease. Maralixibat may reduce absorption of fat-soluble vitamins [see Warnings and Precautions (5.3)]. Monitor FSV levels and supplement FSV intake, if FSV deficiency is observed during lactation. The developmental and health benefits of breastfeeding should be considered along with the mother’s need for LIVMARLI and any potential adverse effects on the breastfed child from LIVMARLI or from the underlying maternal condition.
8.4 Pediatric Use
Additions and/or revisions underlined:
ALGS
The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in Alagille syndrome have been established in pediatric patients aged 3 months of age and older. Use of LIVMARLI in this population is supported by evidence from a study of patients 1 to 15 years of age (N=31) that included 18 weeks of open-label treatment followed by a 4 week placebo-controlled randomized withdrawal period and a subsequent 26-week open-label treatment period. Additional safety information was obtained from four studies in patients up to 21 years of age (N=55) [see Adverse Reactions (6) and Clinical Studies (14.1)]. Use of LIVMARLI in patients 3 to <12 months of age is supported by an open-label, multicenter study of LIVMARLI which showed a similar safety, tolerability and pharmacokinetic profile to patients with ALGS >12 months of age.
The safety and effectiveness of LIVMARLI have not been established in patients with ALGS less than 3 months of age.
PFIC
The safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in PFIC have been established in pediatric patients aged 5 years of age and older. Use of LIVMARLI in this population is supported by evidence from Trial 2 in patients 1 to <18 years of age that included 26 weeks of placebo-controlled safety and efficacy data [see Adverse Reactions (6) and Clinical Studies (14.2)].
The safety and effectiveness of LIVMARLI have not been established in patients with PFIC younger than 12 months of age.
8.5 Geriatric Use
Additions and/or
revisions underlined:
The safety
and effectiveness of LIVMARLI for the treatment of pruritus in ALGS or
PFIC in adult patients, 65 years of age and
older, have not been established.
8.6 Hepatic Impairment
Additions and/or
revisions underlined:
Clinical
studies of LIVMARLI included ALGS or PFIC patients with impaired hepatic
function at baseline. The efficacy and safety in ALGS or PFIC patients
with clinically significant portal hypertension and in patients
with decompensated cirrhosis
have not been established. LIVMARLI is contraindicated in patients with prior or active hepatic
decompensation events [see Dosage and
Administration (2.5), Contraindications (4), Warnings and Precautions (5.1), and Clinical Studies (14)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or
revisions underlined:
Advise the patient or their caregiver(s) to read the FDA-approved patient
labeling (Patient Information and Instructions for Use).
Administration Instructions
Advise patients or their caregivers(s) to:
Take LIVMARLI 30 minutes prior to a meal once or twice daily as prescribed using a calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dispenser) provided by the pharmacist to measure and deliver the prescribed dose accurately [see Dosage and Administration (2.1, 2.2 2.4)].
Take LIVMARLI at least 4 hours before or 4 hours after taking a bile acid binding resin (e.g., cholestyramine, colesevelam, or colestipol) [see Drug Interactions (7.1)].
Store the opened bottle below 30?C (86?F). Discard any unused LIVMARLI 100 days after opening the bottle [see How Supplied/Storage and Handling (16)].
Hepatotoxicity
Advise patients or their caregiver(s) that liver tests should be obtained before starting LIVMARLI and periodically during LIVMARLI therapy. Inform patients or their caregiver(s) of the risk of hepatotoxicity that could be fatal and that they will need to undergo monitoring for liver injury. Instruct patients or their caregiver(s) to immediately report any signs or symptoms of severe liver injury to their healthcare provider [see Warnings and Precautions (5.1)].
Gastrointestinal Adverse Reactions
Advise patients or their caregiver(s) to notify their healthcare provider if they experience a new onset or worsening of gastrointestinal symptoms (abdominal pain, vomiting, bloody stool, and diarrhea) [see Warnings and Precautions (5.2)].
Fat Soluble Vitamin (FSV) Deficiency
Advise patients or their caregiver(s) that INR (for vitamin K) and serum levels of vitamins A, D, E will be obtained before starting treatment and periodically during treatment to assess for FSV deficiency [see Warnings and Precautions (5.3)]. Inform patients or their caregiver(s) that they may bleed more easily, may bleed longer, or have a bone fracture. Advise patients or their caregiver(s) to call their healthcare provider for any signs or symptoms of bleeding or report any fractures.
Additions
and/or revisions underlined:
What is LIVMARLI?
LIVMARLI is a prescription medicine used to treat:
cholestatic pruritus (itch) in patients 3 months of age and older with Alagille syndrome (ALGS).
cholestatic pruritus (itch) in patients 5 years of age and older with progressive familial intrahepatic cholestasis (PFIC).
LIVMARLI is not for use in PFIC type 2 patients who have a severe defect in the bile salt export pump (BSEP) protein.
It is not known if LIVMARLI is safe and effective in children with ALGS who are under 3 months of age.
It is not known if LIVMARLI is safe and effective in children with PFIC who are under 5 years of age.
It is not known if LIVMARLI is safe and effective in adults 65 years of age and older.
…
How should you take LIVMARLI?
Read the Instructions for Use that comes with LIVMARLI for information about the right way to prepare and take LIVMARLI.
Before you take LIVMARLI for the first time, talk to your healthcare provider or pharmacist about how to measure the prescribed dose.
Take LIVMARLI exactly as your healthcare provider tells you to.
Your healthcare provider may start you on a low dose of LIVMARLI and then increase the dose, especially if you have not taken LIVMARLI.
Do not change your dose of LIVMARLI unless your healthcare provider tells you to.
LIVMARLI is taken by mouth, 1 or 2 times each day (if 2 times per day, take in the morning and evening), 30 minutes before a meal.
If you miss a dose of LIVMARLI and you take LIVMARLI 1-time a day:
If it is 12 hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.
If it is more than 12 hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time.
If you miss a dose of LIVMARLI and you take LIVMARLI 2-times a day:
If it is 6 hours or less from the time you usually take LIVMARLI, take the missed dose as soon as possible. Then take your next dose at the usual time.
If it is more than 6 hours from the time you usually take LIVMARLI, do not take the missed dose. Take your next dose at the usual time.
If you take a medicine that lowers cholesterol by binding bile acids, such as cholestyramine, colesevelam, or colestipol, take it at least 4 hours before or 4 hours after you take LIVMARLI. Ask your healthcare provider if you are not sure if you take these medicines.
If you take too much LIVMARLI, call your healthcare provider or go to the nearest emergency room right away.
Throw away any remaining LIVMARLI 100 days after first opening the bottle.
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What are the possible side effects of LIVMARLI?
LIVMARLI can cause serious side effects, including:Liver injury. Changes in certain liver tests are common in patients with ALGS and in patients with PFIC but may worsen during treatment with LIVMARLI. These changes may be a sign of liver injury and can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment with LIVMARLI to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including:
nausea or vomiting
your skin or the white part of your eye turns yellow
dark or brown urine
pain on the right side of your stomach (abdomen)
fullness, bloating, or fluid in your stomach area (ascites)
loss of appetite
bleeding or bruising more easily than normal, including vomiting blood
Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain during treatment. Diarrhea can also cause the loss of too much body fluid (severe dehydration). Your healthcare provider should check your stool for blood and monitor you for too much body fluid loss.
Tell your healthcare provider right away if you have any new or worsening signs or symptoms of stomach and intestinal problems including:
diarrhea
more frequent bowel movements than usual
stools that are black, tarry, sticky, or have blood or mucous
severe stomach-area pain or tenderness
Tell your healthcare provider if you have any signs and symptoms of a loss of too much body fluid including:
vomiting
urinating less often than usual
dizziness
diarrhea
headache
A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat. FSV deficiency is common in patients with ALGS and in patients with PFIC but may worsen during treatment with LIVMARLI. Your healthcare provider should do blood tests before starting and during treatment with LIVMARLI.
Other common side effects of FSV deficiency reported during treatment with LIVMARLI were bone fractures and bleeding.
Your healthcare provider may change your dose, or temporarily or permanently stop treatment with LIVMARLI if you have certain side effects.
These are not all of the possible side effects of LIVMARLI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088.
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03/13/2023 (SUPPL-4)
8 Use in Specific Populations
8.4 Pediatric UseThe safety and effectiveness of LIVMARLI for the treatment of cholestatic pruritus in Alagille syndrome have been established in pediatric patients aged 3 months of age and older. Use of LIVMARLI in this population is supported by evidence from a study of patients 1 to 15 years of age (N=31) that included 18 weeks of open-label treatment followed by a 4 week placebo-controlled randomized withdrawal period and a subsequent 26-week open-label treatment period. Additional safety information was obtained from four studies in patients up to 21 years of age (N=55) [see Adverse Reactions (6) and Clinical Studies (14)]. Use of LIVMARLI in patients 3 to <12 months of age is supported by an open-label, multicenter study of LIVMARLI which showed a similar safety, tolerability and pharmacokinetic profile to patients with ALGS >12 months of age.
The safety and effectiveness of LIVMARLI have not been established in patients less than 3 months of age.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and/or
revisions underlined:
Advise the patient or their
caregiver(s) to read
the FDA-approved patient
labeling (Patient Information and Instructions for Use).
Administration Instructions
Advise patients or their caregivers(s) to:
Take LIVMARLI 30 minutes prior to a meal in the morning using a calibrated measuring device (0.5 mL, 1 mL or 3 mL oral dispenser) to measure and deliver the prescribed dose accurately [see Dosage and Administration (2.1, 2.3)].
Take LIVMARLI at least 4 hours before or 4 hours after taking a bile acid binding resin (e.g., cholestyramine, colesevelam, or colestipol) [see Drug Interactions (7.1)].
Store the opened bottle below 30?C (86?F). Discard any unused LIVMARLI 100 days after opening the bottle [see How Supplied/Storage and Handling (16)].
Liver Test Abnormalities
Advise patients or their caregiver(s) that liver tests should be obtained before starting LIVMARLI and periodically during LIVMARLI therapy, due to the risk of elevation in liver tests and development of liver-related adverse reactions [see Dosage and Administration (2.4) and Warnings and Precautions (5.1, 5.2)].
Gastrointestinal Adverse Reactions
Advise patients or their caregiver(s) to notify their healthcare provider if they experience new onset or worsening of gastrointestinal symptoms [see Warnings and Precautions (5.2)].
Fat Soluble Vitamin (FSV) Deficiency
Advise patients or their caregiver(s) that INR (for vitamin K) and serum levels of vitamins A, D, E will be obtained before starting and periodically during treatment to assess for FSV deficiency [see Warnings and Precautions (5.3)].
Additions
and/or revisions underlined:
What
is LIVMARLI?
LIVMARLI is a prescription medicine used to treat cholestatic pruritus (itch) in patients with Alagille syndrome 3 months of age and older.
It is not known if LIVMARLI is safe and effective in children under 3 months of age.
- It is not known if LIVMARLI is safe and effective in adults 65 years of age and older.
…
How should I take LIVMARLI?
…
- LIVMARLI is taken by mouth, 1 time each day, 30 minutes before a meal in the morning.
…
If you take a medicine that lowers cholesterol by binding bile acids, such as cholestyramine, colesevelam, or colestipol, take it at least 4 hours before or 4 hours after you take LIVMARLI. Ask your healthcare provider if you are not sure if you take these medicines.
- Throw away any remaining LIVMARLI 100 days after first opening the bottle.
…
What are the possible side effects of LIVMARLI?
…
These are not all of the possible side effects of LIVMARLI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088.
…
How should I store LIVMARLI?
Store unopened LIVMARLI at room temperature between 68ºF and 77ºF (20ºC and 25ºC).
- After opening the LIVMARLI bottle, store below 86ºF (30ºC).
Keep LIVMARLI and all medicines out of the reach of children.