naratriptan 2.5 MG Oral Tablet [Amerge]
DRUG INTERACTIONS
7 7.1 Ergot-Containing Drugs Ergot-containing drugs have been reported to cause prolonged vasospastic reactions.
Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and AMERGE within 24 hours of each other is contraindicated.
7.2 Other 5-HT 1 Agonists Concomitant use of other 5-HT 1B/1D agonists (including triptans) within 24 hours of treatment with AMERGE is contraindicated because the risk of vasospastic reactions may be additive.
7.3 Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7)] .
OVERDOSAGE
10 Adverse reactions observed after overdoses of up to 25 mg included increases in blood pressure resulting in lightheadedness, neck tension, tiredness, and loss of coordination.
Also, ischemic ECG changes likely due to coronary artery vasospasm have been reported.
The elimination half-life of naratriptan is about 6 hours [see Clinical Pharmacology (12.3)] ; therefore monitoring of patients after overdose with AMERGE should continue for at least 24 hours or while symptoms or signs persist.
There is no specific antidote to naratriptan.
It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of naratriptan.
DESCRIPTION
11 AMERGE contains naratriptan hydrochloride, a selective 5-HT 1B/1D receptor agonist.
Naratriptan hydrochloride is chemically designated as N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide monohydrochloride, and it has the following structure: The empirical formula is C 17 H 25 N 3 O 2 S•HCl, representing a molecular weight of 371.93.
Naratriptan hydrochloride is a white to pale yellow powder that is readily soluble in water.
Each AMERGE tablet for oral administration contains 1.11 or 2.78 mg of naratriptan hydrochloride, equivalent to 1 or 2.5 mg of naratriptan, respectively.
Each tablet also contains the inactive ingredients croscarmellose sodium; hypromellose; lactose; magnesium stearate; microcrystalline cellulose; triacetin; and titanium dioxide, iron oxide yellow (2.5-mg tablet only), and indigo carmine aluminum lake (FD&C Blue No.
2) (2.5-mg tablet only) for coloring.
Chemical structure
CLINICAL STUDIES
14 The efficacy of AMERGE in the acute treatment of migraine headaches was evaluated in 3 randomized, double-blind, placebo-controlled trials in adult patients (Trials 1, 2, 3).
These trials enrolled adult patients who were predominantly female (86%) and Caucasian (96%) with a mean age of 41 years (range: 18 to 65 years).
In all studies, patients were instructed to treat at least 1 moderate to severe headache.
Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing.
Associated symptoms such as nausea, vomiting, photophobia, and phonophobia were also assessed.
Maintenance of response was assessed for up to 24 hours postdose.
A second dose of AMERGE or other rescue medication to treat migraines was allowed 4 to 24 hours after the initial treatment for recurrent headache.
In all 3 trials, the percentage of patients achieving headache response 4 hours after treatment, the primary outcome measure, was significantly greater among patients receiving AMERGE compared with those who received placebo.
In all trials, response to 2.5 mg was numerically greater than response to 1 mg and in the largest of the 3 trials, there was a statistically significant greater percentage of patients with headache response at 4 hours in the 2.5-mg group compared with the 1-mg group.
The results are summarized in Table 2.
Table 2.
Percentage of Adult Patients with Headache Response (Mild or No Headache) 4 Hours following Treatment AMERGE 1 mg (n = 491) AMERGE 2.5 mg (n = 493) Placebo (n = 395) Trial 1 Trial 2 Trial 3 50% a 52% a 54% a 60% a 66% ab 65% a 34% 27% 32% a P <0.05 compared with placebo.
b P <0.05 compared with 1 mg.
The estimated probability of achieving an initial headache response in adults over the 4 hours following treatment in pooled Trials 1, 2, and 3 is depicted in Figure 1.
Figure 1.
Estimated Probability of Achieving Initial Headache Response within 4 Hours in Pooled Trials 1, 2, and 3 a a The figure shows the probability over time of obtaining headache response (reduction in headache severity from moderate or severe pain to no or mild pain) following treatment with AMERGE.
In this Kaplan-Meier plot, patients not achieving response within 240 minutes were censored at 240 minutes.
For patients with migraine-associated nausea, photophobia, and phonophobia at baseline, there was a lower incidence of these symptoms 4 hours following administration of 1-mg and 2.5-mg AMERGE compared with placebo.
Four to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other rescue medication.
The estimated probability of patients taking a second dose or other rescue medication to treat migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
Figure 2.
Estimated Probability of Patients Taking a Second Dose of AMERGE Tablets or Other Medication to Treat Migraine over the 24 Hours following the Initial Dose of Study Treatment in Pooled Trials 1, 2, and 3 a a Kaplan-Meier plot based on data obtained in the 3 controlled clinical trials (Trials 1, 2, and 3) providing evidence of efficacy with patients not using additional treatments censored at 24 hours.
The plot also includes patients who had no response to the initial dose.
Remedication was discouraged prior to 4 hours postdose.
There is no evidence that doses of 5 mg provided a greater effect than 2.5 mg.
There was no evidence to suggest that treatment with AMERGE was associated with an increase in the severity or frequency of migraine attacks.
The efficacy of AMERGE was unaffected by presence of aura; gender, age, or weight of the subject; oral contraceptive use; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants).
There was insufficient data to assess the impact of race on efficacy.
Figure 1 Figure 2
HOW SUPPLIED
16 /STORAGE AND HANDLING AMERGE tablets containing 1 mg and 2.5 mg of naratriptan (base) as the hydrochloride salt.
AMERGE tablets, 1 mg, are white, D-shaped, film-coated tablets debossed with “GX CE3” on one side in blister packs of 9 tablets (NDC 0173-0561-00).
AMERGE tablets, 2.5 mg, are green, D-shaped, film-coated tablets debossed with “GX CE5” on one side in blister packs of 9 tablets (NDC 0173-0562-00).
Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP].
GERIATRIC USE
8.5 Geriatric Use Clinical trials of AMERGE did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Naratriptan is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in elderly patients who have reduced renal function.
In addition, elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly.
A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving AMERGE [see Warnings and Precautions (5.1)] .
DOSAGE FORMS AND STRENGTHS
3 1-mg white tablets, D-shaped, film-coated, and debossed with “GX CE3” 2.5-mg green tablets, D-shaped, film-coated, and debossed with “GX CE5” Tablets: 1 mg and 2.5 mg ( 3 , 16 )
MECHANISM OF ACTION
12.1 Mechanism of Action Naratriptan binds with high affinity to human cloned 5-HT 1B/1D receptors.
Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (including substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system.
The therapeutic activity of AMERGE for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
INDICATIONS AND USAGE
1 AMERGE is indicated for the acute treatment of migraine with or without aura in adults.
Limitations of Use • Use only if a clear diagnosis of migraine has been established.
If a patient has no response to the first migraine attack treated with AMERGE, reconsider the diagnosis of migraine before AMERGE is administered to treat any subsequent attacks.
• AMERGE is not indicated for the prevention of migraine attacks.
• Safety and effectiveness of AMERGE have not been established for cluster headache.
AMERGE is a serotonin (5-HT 1B/1D ) receptor agonist (triptan) indicated for the acute treatment of migraine with or without aura in adults.
( 1 ) Limitations of Use • Use only if a clear diagnosis of migraine has been established.
( 1 ) • Not indicated for the prophylactic therapy of migraine attacks.
( 1 ) • Not indicated for the treatment of cluster headache.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Therefore, AMERGE is not recommended for use in patients younger than 18 years of age.
One controlled clinical trial evaluated AMERGE (0.25 to 2.5 mg) in 300 adolescent migraineurs aged 12 to 17 years who received at least 1 dose of AMERGE for an acute migraine.
In this study, 54% of the patients were female and 89% were Caucasian.
There were no statistically significant differences between any of the treatment groups.
The headache response rates at 4 hours (n) were 65% (n = 74), 67% (n = 78), and 64% (n = 70) for placebo, 1-mg, and 2.5-mg groups, respectively.
This trial did not establish the efficacy of AMERGE compared with placebo in the treatment of migraine in adolescents.
Adverse reactions observed in this clinical trial were similar in nature to those reported in clinical trials in adults.
PREGNANCY
8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of AMERGE in pregnant women.
Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have documented outcomes in women exposed to naratriptan during pregnancy; however, due to small sample sizes, no definitive conclusions can be drawn regarding the risk of birth defects following exposure to naratriptan [see Data] .
In animal studies, naratriptan produced developmental toxicity (including embryolethality and fetal abnormalities) when administered to pregnant rats and rabbits.
The lowest doses producing evidence of developmental toxicity in animals were associated with plasma exposures 2.5 (rabbit) to 11 (rat) times that in humans at the maximum recommended daily dose (MRDD) [see Data] .
In the U.S.
general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and of miscarriage was 17%, which were similar to rates reported in women without migraine.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Several studies have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.
Data Human Data: The numbers of exposed pregnancy outcomes accumulated during the Sumatriptan/Naratriptan/Treximet (sumatriptan and naproxen sodium) Pregnancy Registry, a population-based international prospective study that collected data from October 1997 to September 2012, and smaller observational studies, were insufficient to define a level of risk for naratriptan in pregnant women.
The Registry documented outcomes of 57 infants and fetuses exposed to naratriptan during pregnancy (52 exposed during the first trimester and 5 exposed during the second trimester).
The occurrence of major birth defects (excluding fetal deaths and induced abortions without reported defects and all spontaneous pregnancy losses) during first-trimester exposure to naratriptan was 2.2% (1/46 [95% CI: 0.1% to 13.0%]) and during any trimester of exposure was 2.0% (1/51 [95% CI: 0.1% to 11.8%]).
Seven infants were exposed to both naratriptan and sumatriptan in utero, and one of these infants with first-trimester exposure was born with a major birth defect (ventricular septal defect).
The sample size in this study had 80% power to detect at least a 3.8- to 4.6-fold increase in the rate of major malformations.
In a study using data from the Swedish Medical Birth Register, women who used triptans or ergots during pregnancy were compared with women who did not.
Of the 22 births with first-trimester exposure to naratriptan, one infant was born with a malformation (congenital deformity of the hand).
Animal Data: When naratriptan was administered to pregnant rats during the period of organogenesis at doses of 10, 60, or 340 mg/kg/day, there was a dose-related increase in embryonic death; incidences of fetal structural variations (incomplete/irregular ossification of skull bones, sternebrae, ribs) were increased at all doses.
The maternal plasma exposures (AUC) at these doses were approximately 11, 70, and 470 times the exposure in humans at the MRDD.
The high dose was maternally toxic, as evidenced by decreased maternal body weight gain during gestation.
A no-effect dose for developmental toxicity in rats exposed during organogenesis was not established.
When naratriptan was administered orally (1, 5, or 30 mg/kg/day) to pregnant Dutch rabbits throughout organogenesis, the incidence of a specific fetal skeletal malformation (fused sternebrae) was increased at the high dose, the incidence of fetal variations (major blood vessel variations, supernumerary ribs, incomplete skeletal ossification) was increased at the mid and high doses, and embryonic death was increased at all doses (4, 20, and 120 times, respectively, the MRDD on a body surface area basis).
Maternal toxicity (decreased body weight gain) was evident at the high dose.
In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day throughout organogenesis), decreased fetal weights and increased incidences of fetal skeletal variations were observed at all doses (maternal exposures equivalent to 2.5, 19, and 140 times exposure in humans receiving the MRDD), while maternal body weight gain was reduced at 5 mg/kg or greater.
A no-effect dose for developmental toxicity in rabbits exposed during organogenesis was not established.
When female rats were treated orally with naratriptan (10, 60, or 340 mg/kg/day) during late gestation and lactation, offspring behavioral impairment (tremors) and decreased offspring viability and growth were observed at doses of 60 mg/kg or greater, while maternal toxicity occurred only at the highest dose.
Maternal exposures at the no-effect dose for developmental effects in this study were approximately 11 times the exposure in humans receiving the MRDD.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Myocardial ischemia/infarction and Prinzmetal’s angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors.
( 5.1 ) • Arrhythmias: Discontinue AMERGE if occurs.
( 5.2 ) • Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not associated with myocardial ischemia; evaluate for CAD in patients at high risk.
( 5.3 ) • Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue AMERGE if occurs.
( 5.4 ) • Gastrointestinal ischemic reactions and peripheral vasospastic reactions: Discontinue AMERGE if occurs.
( 5.5 ) • Medication overuse headache: Detoxification may be necessary.
( 5.6 ) • Serotonin syndrome: Discontinue AMERGE if occurs.
( 5.7 ) 5.1 Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina AMERGE is contraindicated in patients with ischemic or vasospastic CAD.
There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of AMERGE.
Some of these reactions occurred in patients without known CAD.
AMERGE may cause coronary artery vasospasm (Prinzmetal’s angina) even in patients without a history of CAD.
Perform a cardiovascular evaluation in triptan-naive patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving AMERGE.
If there is evidence of CAD or coronary artery vasospasm, AMERGE is contraindicated.
For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of AMERGE in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of AMERGE.
For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of AMERGE.
5.2 Arrhythmias Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT 1 agonists.
Discontinue AMERGE if these disturbances occur.
AMERGE is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders.
5.3 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with AMERGE and are usually non-cardiac in origin.
However, perform a cardiac evaluation if these patients are at high cardiac risk.
5-HT 1 agonists, including AMERGE, are contraindicated in patients with CAD and those with Prinzmetal’s variant angina.
5.4 Cerebrovascular Events Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT 1 agonists, and some have resulted in fatalities.
In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT 1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not.
Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA).
Discontinue AMERGE if a cerebrovascular event occurs.
Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical for migraine, exclude other potentially serious neurological conditions.
AMERGE is contraindicated in patients with a history of stroke or TIA.
5.5 Other Vasospasm Reactions AMERGE may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome.
In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT 1 agonist, rule out a vasospastic reaction before receiving additional doses of AMERGE.
Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT 1 agonists.
Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT 1 agonists have not been clearly established.
5.6 Medication Overuse Headache Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache).
Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks.
Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
5.7 Serotonin Syndrome Serotonin syndrome may occur with AMERGE, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors [see Drug Interactions (7.3)] .
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication.
Discontinue AMERGE if serotonin syndrome is suspected.
5.8 Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT 1 agonists, including patients without a history of hypertension.
Monitor blood pressure in patients treated with AMERGE.
AMERGE is contraindicated in patients with uncontrolled hypertension.
5.9 Anaphylactic Reactions There have been reports of anaphylaxis and hypersensitivity reactions, including angioedema, in patients receiving AMERGE.
Such reactions can be life threatening or fatal.
In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens.
AMERGE is contraindicated in patients with a history of hypersensitivity reaction to AMERGE.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events Inform patients that AMERGE may cause serious cardiovascular side effects such as myocardial infarction or stroke.
Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech and should ask for medical advice if any indicative sign or symptoms are observed.
Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, 5.8)] .
Anaphylactic Reactions Inform patients that anaphylactic reactions have occurred in patients receiving AMERGE.
Such reactions can be life-threatening or fatal.
In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens [see Contraindications (4), Warnings and Precautions (5.9)] .
Concomitant Use with Other Triptans or Ergot Medications Inform patients that use of AMERGE within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated [see Contraindications (4), Drug Interactions (7.1, 7.2)] .
Serotonin Syndrome Caution patients about the risk of serotonin syndrome with the use of AMERGE or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7), Drug Interactions (7.3)] .
Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)] .
Pregnancy Advise patients to notify their healthcare provider if they become pregnant during treatment or intend to become pregnant [see Use in Specific Populations (8.1)] .
Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2)] .
Ability to Perform Complex Tasks Treatment with AMERGE may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of AMERGE.
AMERGE is a trademark owned by or licensed to the GSK group of companies.
The other brand listed is a trademark owned by or licensed to its owner and is not owned by or licensed to the GSK group of companies.
The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products.
Distributed by: GlaxoSmithKline Research Triangle Park, NC 27709 ©2020 GSK group of companies or its licensor.
AMG:7PI
DOSAGE AND ADMINISTRATION
2 • Recommended dose: 1 mg or 2.5 mg.
( 2.1 ) • May repeat dose after 4 hours if needed; not to exceed 5 mg in any 24-hour period.
( 2.1 ) • Mild or moderate renal or hepatic impairment: recommended starting dose is 1 mg not to exceed 2.5 mg in any 24-hour period.
( 2.2 , 2.3 ) 2.1 Dosing Information The recommended dose of AMERGE is 1 mg or 2.5 mg.
If the migraine returns or if the patient has only partial response, the dose may be repeated once after 4 hours, for a maximum dose of 5 mg in a 24-hour period.
The safety of treating an average of more than 4 migraine attacks in a 30‑day period has not been established.
2.2 Dosage Adjustment in Patients with Renal Impairment AMERGE is contraindicated in patients with severe renal impairment (creatinine clearance: <15 mL/min) because of decreased clearance of the drug [see Contraindications (4), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] .
In patients with mild to moderate renal impairment, the maximum daily dose should not exceed 2.5 mg over a 24‑hour period and a 1-mg starting dose is recommended [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] .
2.3 Dosage Adjustment in Patients with Hepatic Impairment AMERGE is contraindicated in patients with severe hepatic impairment (Child-Pugh Grade C) because of decreased clearance [see Contraindications (4), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] .
In patients with mild or moderate hepatic impairment (Child-Pugh Grade A or B), the maximum daily dose should not exceed 2.5 mg over a 24-hour period and a 1-mg starting dose is recommended [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] .