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NURTEC ODT
(rimegepant) Orally Disintegrating Tablets, for Sublingual or Oral Use
NURTEC ODT contains rimegepant sulfate, a calcitonin gene-related peptide receptor antagonist. Rimegepant sulfate is described chemically as (5S,6S,9R)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1Himidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate sesquihydrate and its structural formula is:
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Its empirical formula is C28H28F2N6O3 0.5 H2SO4 1.5 H2O, representing a molecular weight of  610.63. Rimegepant free base has a molecular weight of 534.56. Rimegepant sulfate is a white to off-white, crystalline solid that is slightly soluble in water.
NURTEC ODT (orally disintegrating tablets) is for sublingual or oral use and contains 85.65 mg rimegepant sulfate, equivalent to 75 mg rimegepant free base, and the following inactive ingredients: benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin.
NURTEC ODT is indicated for the acute treatment of migraine with or without aura in adults.
NURTEC ODT is not indicated for the preventive treatment of migraine.
The recommended dose of NURTEC ODT is 75 mg taken orally.
The maximum dose in a 24-hour period is 75 mg. The safety of treating more than 15 migraines in a 30-day period has not been established.
Instruct the patient on the following administration instructions:
Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A, which may lead to loss of efficacy of NURTEC ODT [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
Avoid concomitant administration of NURTEC ODT with inhibitors of P-gp or BCRP [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
Orally disintegrating tablets: white to off-white, circular, and debossed with the logo, each containing 75 mg of rimegepant.
NURTEC ODT 75 mg orally disintegrating tablets are white to off-white, circular, debossed with the symbol , and supplied in cartons containing a blister pack of 8 orally disintegrating tablets. Each ODT contains 75 mg rimegepant.
NDC: 72618-3000-2
Store NURTEC ODT at controlled room temperature, 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].
Manufactured for: Biohaven Pharmaceuticals, Inc. New Haven, CT 06510 USA. Revised: Feb 2020
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of NURTEC ODT has been evaluated in a randomized, double-blind, placebo-controlled trial (Study 1) in 682 patients with migraine who received one 75 mg dose of NURTEC ODT [see Clinical Studies]. Approximately 85% were female, 74% were White, 21% were Black, and 17% were Hispanic or Latino. The mean age at study entry was 40 years (range 18-75 years of age).
Long-term safety was assessed in an open-label extension study using a different oral dosage form of rimegepant. That study evaluated 1,798 patients, dosing intermittently for up to one year, including 1,131 patients who were exposed to rimegepant 75 mg for at least 6 months, and 863 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month.
The most common adverse reaction in Study 1 was nausea (2% in patients who received NURTEC ODT compared to 0.4% of patients who received placebo).
Hypersensitivity, including dyspnea and severe rash, occurred in less than 1% of patients treated with NURTEC ODT [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 results in a significant increase in rimegepant exposure. Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 [see CLINICAL PHARMACOLOGY].
Concomitant administration of NURTEC ODT with moderate inhibitors of CYP3A4 may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4 [see CLINICAL PHARMACOLOGY].
Concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A can result in a significant reduction in rimegepant exposure, which may lead to loss of efficacy of NURTEC ODT. Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A [see CLINICAL PHARMACOLOGY].
Rimegepant is a substrate of P-gp and BCRP efflux transporters. Concomitant administration of NURTEC ODT with inhibitors of P-gp or BCRP may result in a significant increase in rimegepant exposure [see CLINICAL PHARMACOLOGY]. Avoid NURTEC ODT with inhibitors of P-gp or BCRP.
Included as part of the PRECAUTIONS section.
Hypersensitivity reactions, including dyspnea and rash, have occurred with NURTEC ODT in clinical studies. Hypersensitivity reactions can occur days after administration, and delayed serious hypersensitivity has occurred. If a hypersensitivity reaction occurs, discontinue NURTEC ODT and initiate appropriate therapy [see CONTRAINDICATIONS].
Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION).
Instruct patients not to remove the blister from the outer aluminum pouch until ready to use the orally disintegrating tablet inside [see DOSAGE AND ADMINISTRATION].
Inform patients about the signs and symptoms of hypersensitivity reactions and that these reactions can occur days after administration of NURTEC ODT. Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur [see WARNINGS AND PRECAUTIONS].
Oral administration of rimegepant to Tg.rasH2 mice (0, 10, 100, or 300 mg/k/day) for 26 weeks and to rats (0, 5, 20, or 45 mg/kg/day) for 91-100 weeks resulted in no evidence of drug-induced tumors in either species. In rats, the plasma exposure (AUC) at the highest dose tested (45 mg/kg/day) was approximately 30 times that in humans at the maximum recommended human dose (MRHD) of 75 mg/day.
Rimegepant was negative in in vitro (bacterial reverse-mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (rat micronucleus) assays.
Oral administration of rimegepant (0, 30, 60, or 150 mg/kg/day) to male and female rats prior to and during mating and continuing in females to gestation day (GD) 7 resulted in uterine atrophy at all doses and reduced fertility at the highest dose tested. In a second fertility study testing lower doses (0, 5, 15, or 25 mg/kg/day), no adverse effects on fertility, uterine histopathology, or early embryonic development were observed. The no-effect dose for impairment of fertility and early embryonic development in rats (25 mg/kg/day) was associated with plasma drug exposures (AUC) approximately 15 times that in humans at the MRHD.
There are no adequate data on the developmental risk associated with the use of NURTEC ODT in pregnant women. In animal studies, oral administration of rimegepant during organogenesis resulted in adverse effects on development in rats (decreased fetal body weight and increased incidence of fetal variations) at exposures greater than those used clinically and which were associated with maternal toxicity. The evaluation of developmental effects following oral administration of rimegepant throughout pregnancy and lactation was inadequate (see Data).
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. The estimated rate of major birth defects (2.2 to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Published data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.
Animal Data
Oral administration of rimegepant (0, 10, 60, or 300 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreased fetal body weight and an increased incidence of fetal variations at the highest dose tested (300 mg/kg/day), which was associated with maternal toxicity. Plasma exposures (AUC) at the no-effect dose (60 mg/kg/day) for adverse effects on embryofetal development were approximately 45 times that in humans at the maximum recommended human dose (MRHD) of 75 mg/day.
Oral administration of rimegepant (0, 10, 25, or 50 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in no adverse effects on embryofetal development. The highest dose tested (50 mg/kg/day) was associated with plasma exposures (AUC) approximately 10 times that in humans at the MRHD.
The prenatal and postnatal development study in rats, in which rimegepant (0, 10, 25, or 60 mg/kg/day) was orally administered throughout gestation and lactation, was inadequate to assess for adverse effects of rimegepant during these periods of development.
There are no data on the presence of rimegepant or its metabolites in human milk, the effects of rimegepant on the breastfed infant, or the effects of rimegepant on milk production. There are no animal data on the excretion of rimegepant in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NURTEC ODT and any potential adverse effects on the breastfed infant from NURTEC ODT or from the underlying maternal condition.
Safety and effectiveness in pediatric patients have not been established.
In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects. Clinical studies of NURTEC ODT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
No dosage adjustment of NURTEC ODT is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Plasma concentrations of rimegepant were significantly higher in subjects with severe (Child-Pugh C) hepatic impairment. Avoid use of NURTEC ODT in patients with severe hepatic impairment [see CLINICAL PHARMACOLOGY].
No dosage adjustment of NURTEC ODT is required in patients with mild, moderate, or severe renal impairment. NURTEC ODT has not been studied in patients with end-stage renal disease and in patients on dialysis. Avoid use of NURTEC ODT in patients with end-stage renal disease (CLcr < 15 mL/min) [see CLINICAL PHARMACOLOGY].
There is limited clinical experience with NURTEC ODT overdosage. Treatment of an overdose of NURTEC ODT should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. No specific antidote for the treatment of rimegepant overdose is available. Rimegepant is unlikely to be significantly removed by dialysis because of high serum protein binding [see CLINICAL PHARMACOLOGY].
NURTEC ODT is contraindicated in patients with a history of hypersensitivity reaction to rimegepant, NURTEC ODT, or any of its components. Delayed serious hypersensitivity has occurred [see WARNINGS AND PRECAUTIONS].
Rimegepant is a calcitonin gene-related peptide receptor antagonist.
The relationship between pharmacodynamic activity and the mechanism(s) by which rimegepant exerts its clinical effects is unknown.
No clinically relevant differences in resting blood pressure were observed when rimegepant was concomitantly administered with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) compared with sumatriptan alone to healthy volunteers.
At a single dose 4 times the recommended dose, rimegepant does not prolong the QT interval to any clinically relevant extent.
Following oral administration of NURTEC ODT, rimegepant is absorbed with the maximum concentration at 1.5 hours. The absolute oral bioavailability of rimegepant is approximately 64%.
Effects Of Food
Following administration of NURTEC ODT under fed condition with a high-fat meal, Tmax was delayed by 1 hour and resulted in a 42 to 53% reduction in Cmax and a 32 to 38% reduction in AUC. NURTEC ODT was administered without regard to food in clinical safety and efficacy studies. The impact of the reduction in rimegepant exposure because of administration with food on its efficacy is unknown.
The steady state volume of distribution of rimegepant is 120 L. Plasma protein binding of rimegepant is approximately 96%.
Metabolism
Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Rimegepant is primarily eliminated in unchanged form (~77% of the dose) with no major metabolites (i.e., > 10%) detected in plasma.
The elimination half-life of rimegepant is approximately 11 hours in healthy subjects. Following oral administration of [14C]-rimegepant to healthy male subjects, 78% of the total radioactivity was recovered in feces and 24% in urine. Unchanged rimegepant is the major single component in excreted feces (42%) and urine (51%).
In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild (estimated creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr 15-29 mL/min) renal impairment to that with normal subjects (healthy matched control), the exposure of rimegepant following single 75 mg dose was approximately 40% higher in subjects with moderate renal impairment. However, there was no clinically meaningful difference in the exposure of rimegepant in subjects with severe renal impairment compared to subjects with normal renal function (CLcr >=90mL/min). NURTEC ODT has not been studied in patients with end-stage renal disease (CLcr < 15 mL/min) [see Use In Specific Populations].
In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild, moderate, and severe hepatic impairment to that with normal subjects (healthy matched control), the exposure of rimegepant (Cmax and AUC) following single 75 mg dose was approximately 2-fold higher in subjects with severe impairment (Child-Pugh class C). There were no clinically meaningful differences in the exposure of rimegepant in subjects with mild (Child-Pugh class A) and moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function [see Use In Specific Populations].
No clinically significant differences in the pharmacokinetics of rimegepant were observed based on age, sex, race/ethnicity, body weight, or CYP2C9 genotype [see CLINICAL PHARMACOLOGY].
Enzymes
Rimegepant is a substrate of CYP3A4 and CYP2C9 (see In Vivo Studies). Rimegepant is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or UGT1A1 at clinically relevant concentrations. However, rimegepant is a weak inhibitor of CYP3A4 with time-dependent inhibition. Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.
Transporters
Rimegepant is a substrate of P-gp and BCRP. Concomitant administration of inhibitors of P-gp or BCRP may increase the exposure of rimegepant [see DRUG INTERACTIONS]. No dedicated drug interaction study was conducted to assess their effects on the pharmacokinetics of rimegepant.
Rimegepant is not a substrate of OATP1B1 or OATP1B3. Considering its low renal clearance, rimegepant was not evaluated as a substrate of the OAT1, OAT3, OCT2, MATE1, or MATE2-K.
Rimegepant is not an inhibitor of P-gp, BCRP, OAT1, or MATE2-K at clinically relevant concentrations. It is a weak inhibitor of OATP1B1 and OAT3. Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. No clinical drug interactions are expected for NURTEC ODT with these transporters at clinically relevant concentrations.
CYP3A4 Inhibitors
In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with itraconazole, a strong CYP3A4 inhibitor, at steady state resulted in increased exposures of rimegepant (AUC by 4-fold and Cmax by ~1.5-fold) [see DRUG INTERACTIONS]. No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a weak inhibitor of CYP3A4 on the pharmacokinetics of rimegepant. The concomitant administration of rimegepant with a moderate inhibitor of CYP3A4 may increase rimegepant exposures (AUC) by less than 2-fold [see DRUG INTERACTIONS]. Concomitant administration of rimegepant with a weak inhibitor of CYP3A4 is not expected to have a clinically significant impact on rimegepant exposures.
CYP3A Inducers
In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with rifampin, a strong CYP3A4 inducer, at steady state resulted in decreased exposures of rimegepant (AUC by 80% and Cmax by 64%), which may lead to loss of efficacy [see DRUG INTERACTIONS]. No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a moderate or weak inducer of CYP3A4 on the pharmacokinetics of rimegepant. Since rimegepant is a moderately sensitive substrate for CYP3A4, drugs that are moderate inducers of CYP3A4 can also cause significant reduction in rimegepant exposure resulting in loss of efficacy [see DRUG INTERACTIONS]. Clinically significant interaction is not expected with concomitant administration of weak inducers of CYP3A4 and rimegepant.
CYP2C9 Inhibitors
In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with fluconazole, a combined moderate CYP3A4 and CYP2C9 inhibitor, resulted in increased exposures of rimegepant (AUC by 1.8-fold) with no relevant effect on Cmax. Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Increase in the exposure of rimegepant can be attributed to combined inhibition of CYP2C9 and CYP3A4 with fluconazole administration suggesting a minor contribution from CYP2C9. Thus, CYP2C9 inhibition alone is not expected to significantly affect rimegepant exposures.
Other Drugs
No significant pharmacokinetic interactions were observed when rimegepant was concomitantly administered with oral contraceptives (norelgestromin, ethinyl estradiol), midazolam (a sensitive CY3A4 substrate), or sumatriptan [see CLINICAL PHARMACOLOGY].
CYP2C9 activity is reduced in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Rimegepant Cmax and AUC0-inf were similar in CYP2C9 intermediate metabolizers (i.e., *1/*2, *2/*2, *1/*3, n=43) as compared to normal metabolizers (i.e., *1/*1, N=72). Adequate PK data are not available from CYP2C9 poor metabolizers (i.e., *2/*3). Since the contribution of CYP2C9 to rimegepant metabolism is considered minor, CYP2C9 polymorphism is not expected to significantly affect its exposure.
The efficacy of NURTEC ODT for the acute treatment of migraine with and without aura in adults was demonstrated in a randomized, double-blind, placebo-controlled trial: Study 1 (NCT03461757). The study randomized patients to 75 mg of NURTEC ODT (N=732) or placebo (N=734). Patients were instructed to treat a migraine of moderate to severe headache pain intensity. Rescue medication (i.e., NSAIDs, acetaminophen, and/or an antiemetic) was allowed 2 hours after the initial treatment. Other forms of rescue medication such as triptans were not allowed within 48 hours of initial treatment. Approximately 14% of patients were taking preventive medications for migraine at baseline. None of the patients in Study 1 were on concomitant preventive medication that act on the CGRP pathway.
The primary efficacy analyses were conducted in patients who treated a migraine with moderate to severe pain. NURTEC ODT 75 mg demonstrated an effect on pain freedom and most bothersome symptom (MBS) freedom at two hours after dosing, compared to placebo. Pain freedom was defined as a reduction of moderate or severe headache pain to no headache pain, and MBS freedom was defined as the absence of the self-identified MBS (i.e., photophobia, phonophobia, or nausea). Among patients who selected an MBS, the most commonly selected symptom was photophobia (54%), followed by nausea (28%), and phonophobia (15%).
In Study 1, the percentage of patients achieving headache pain freedom and MBS freedom two hours after a single dose was statistically significantly greater in patients who received NURTEC ODT compared to those who received placebo (Table 1).
Table 1: Migraine Efficacy Endpoints for Study 1
| Study 1 | ||
| NURTEC ODT 75 mg | Placebo | |
| Pain Free at 2 hours | ||
| n/N* | 142/669 | 74/682 |
| % Responders | 21.2 | 10.9 |
| Difference from placebo (%) | 10.3 | |
| p-value | <0.001 | |
| MBS Free at 2 hours | ||
| n/N* | 235/669 | 183/682 |
| % Responders | 35.1 | 26.8 |
| Difference from placebo (%) | 8.3 | |
| p-value | 0.001 | |
| *n=number of responders/N=number of patients in that treatment group | ||
Figure 1 presents the percentage of patients achieving migraine pain freedom within 2 hours following treatment in Study 1.
Figure 1: Percentage of Patients Achieving Pain Freedom within 2 Hours in Study 1
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Figure 2 presents the percentage of patients achieving MBS freedom within 2 hours in Study 1.
Figure 2: Percentage of Patients Achieving MBS Freedom within 2 Hours in Study 1
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In Study 1, statistically significant effects of NURTEC ODT compared to placebo were demonstrated for the additional efficacy endpoints of pain relief at 2 hours, sustained pain freedom 2-48 hours, use of rescue medication within 24 hours, and the percentage of patients reporting normal function at two hours after dosing (Table 2). Pain relief was defined as a reduction in migraine pain from moderate or severe severity to mild or none. The measurement of the percentage of patients reporting normal function at two hours after dosing was derived from a single item questionnaire, asking patients to select one response on a 4-point scale; normal function, mild impairment, severe impairment, or required bedrest.
Table 2: Additional Migraine Efficacy Endpoints in Study 1
| Study 1 | ||
| NURTEC ODT 75 mg | Placebo | |
| Pain Relief at 2 hours | ||
| n/N* | 397/669 | 295/682 |
| % Responders | 59.3 | 43.3 |
| Difference from placebo | 16.1 | |
| p-value | <0.001 | |
| Sustained Pain Freedom 2-48 hours | ||
| n/N* | 90/669 | 37/682 |
| % Responders | 13.5 | 5.4 |
| Difference from placebo | 8.0 | |
| p-value | <0.001 | |
| Use of Rescue Medication within 24 hours** | ||
| n/N* | 95/669 | 199/682 |
| % Responders | 14.2 | 29.2 |
| Difference from placebo | -15.0 | |
| p-value | <0.001 | |
| Percentage of Patients Reporting Normal Function at 2 hours | ||
| n/N* | 255/669 | 176/682 |
| % Responders | 38.1 | 25.8 |
| Difference from placebo | 12.3 | |
| p-value | <0.001 | |
| *n=number of responders/N=number of patients in that treatment group **This analysis includes only the use of NSAIDs, acetaminophen, or antiemetics, within 24 hours post-dose; the use of triptans, or other acute migraine medication, was not allowed. | ||
The incidence of photophobia and phonophobia was reduced following administration of NURTEC ODT 75 mg as compared to placebo.
NURTEC™ ODT
(NUR-tek)
(rimegepant sulfate) orally disintegrating tablets (ODT)
What is NURTEC ODT?
NURTEC ODT is a prescription medicine used for the acute treatment of migraine attacks with or without aura in adults.
Do not take NURTEC ODT if you are:
See the end of this leaflet for a complete list of ingredients in NURTEC ODT.
Before you take NURTEC ODT, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I take NURTEC ODT?
What are the possible side effects of NURTEC ODT?
NURTEC ODT may cause serious side effects including:
The most common side effect of NURTEC ODT is:
This is not the only possible side effect of NURTEC ODT.
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 NURTEC ODT?
Keep NURTEC ODT and all medicines out of the reach of children.
General information about the safe and effective use of NURTEC ODT:
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NURTEC ODT for a condition for which it was not prescribed. Do not give NURTEC ODT to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NURTEC ODT that is written for health professionals.
What are the ingredients in NURTEC ODT?
Active ingredient in NURTEC ODT: rimegepant
Inactive ingredients in NURTEC ODT: benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin
This Patient Information has been approved by the U.S. Food and Drug Administration.
