Cut to the core with symptom relief that’s delivered differently
With its unique PROdrug formulation, Horizant® levels in circulation directly correspond to the dose1-3
Consider the PROs you may experience with Horizant®: prolonged absorption, AUC exposure that increases predictably in proportion to the dose, and PROdrug delivery1,3
PROLONGED
- Horizant® is recognized by transporters distributed throughout the intestinal tract for prolonged, 24-hour absorption1,3
PROPORTIONAL
- Horizant® is formulated for enhanced absorption so that levels in circulation increase predictably in proportion to the prescribed dose1,3
PRODRUG
- As a PROdrug, Horizant® has a unique delivery mechanism3
The clinical significance of the PK data for Horizant® and gabapentin is unknown.
High-capacity transporters absorb Horizant® throughout the intestinal tract3
Absorption with Horizant®6
Adapted from Lal R, et al. Ther Drug Monit. 2022;44(3):449.
Horizant® is thought to be absorbed by high-capacity nutrient transporters in the intestinal lumen. These transporters are located throughout the entire intestinal tract. Horizant® is converted to gabapentin as it is absorbed into systemic circulation in the bloodstream.1,3
- The conventional gabapentin absorption pathway may become saturated, limiting the amount of drug that reaches systemic circulation3
- Horizant® is a PROdrug recognized by high-capacity nutrient transporters located through the intestinal tract3
- Horizant®’s absorption pathway does not become saturated at clinically relevant doses, enabling a greater proportion of the dose of drug to reach systemic circulation3
Horizant® is not interchangeable with other gabapentin products.1
The clinical significance of the PK data for Horizant® and gabapentin is unknown.
The unique absorption of Horizant® enables extended and dose-proportional exposure3,7
- To help patients achieve the optimal dose, a pathway is needed to increase drug levels that is not dependent on increasing the dose3,7,8
- After administering approximate equimolar doses in a crossover study, Horizant® reaches higher Cmax and greater AUC compared with conventional gabapentin3
Approximate equimolar doses in the same healthy adults3
Twenty-four hours after administering approximate equimolar doses of Horizant® (1200 mg, fed state) and gabapentin (600 mg, fasted state), Horizant® demonstrated a higher Cmax and greater AUC.
*The recommended dosage of Horizant® for RLS is 600 mg taken once daily with food at about 5 PM. A daily dose of 1200 mg provided no additional benefit compared with the 600 mg dose and caused an increase in adverse reactions. Patients with creatinine clearance <60 mL/min have a different dosing regimen.1
†The molecular weight of Horizant® is ~2 times that of gabapentin: Two 600 mg doses of Horizant® contain ~626 mg of gabapentin.3
‡Data for fasted state are not available, as Horizant® Prescribing Information states that it should be taken with food.1
Conventional gabapentin levels may be limited by saturation of its absorption pathway3
Absorption with conventional gabapentin3
Gabapentin is thought to be absorbed only in the upper intestinal tract by low-capacity nutrient transporters that limit how much of the drug reaches systemic circulation.3
- Saturation of the transporters limits how much gabapentin reaches systemic circulation3
- Saturation varies between individuals and therefore makes the bioavailability difficult to predict3,6
- Conventional gabapentin is thought to be absorbed in the upper small intestine via a low-capacity transporter3
Horizant® exposure was shown to increase in proportion with the dose3
- Because Horizant® is absorbed differently, plasma concentration increases predictably as the dose increases3
Dose proportionality of Horizant® vs gabapentin AUC in blood after single oral doses3
Adapted from Cundy KC, et al. J Clin Pharmacol. 2008;48(12):1383.
Gabapentin AUC exposure was less than dose-proportional in a PK study evaluating dose proportionality of Horizant® vs gabapentin AUC in blood after single oral doses. Gabapentin blood levels were shown to reach a maximum value independent of the dose. This is consistent with saturation of absorption. With Horizant®, exposure to gabapentin (AUC[0-∞]) in blood was proportional to the oral dose over doses ranging from 350 to 2800 mg (182 mg to 1460 mg-equivalents of gabapentin).3
Horizant® was designed as an extended-release gabapentin formulation with enhanced absorption1,3
Bioavailability of Horizant® vs conventional gabapentin3*,†
The pharmacokinetics of Horizant® were compared with those of conventional gabapentin in a crossover study of the same healthy adults. Patients (N=12) were randomized to 3 different treatment sequences, each receiving 3 doses: a 626 mg gabapentin-equivalent dose of Horizant® with food, a 626 mg gabapentin-equivalent dose of Horizant® without food, and a 600 mg dose of conventional gabapentin without food. Patients had a 7-day washout period between doses. Data for fasted state are not available, as Horizant® Prescribing Information states that it should be taken with food.3
- This may contribute to THE difference in bioavailability of Horizant® compared to conventional gabapentin1,2
*Horizant® 1200 mg (two 600 mg tablets, equivalent in total to 626 mg of conventional gabapentin) taken with food vs conventional gabapentin 600 mg taken without food. Data for fasted state are not available, as Horizant® Prescribing Information states that it should be taken with food.1
†The molecular weight of Horizant® is ~2 times that of gabapentin: Two 600 mg doses of Horizant® contain ~626 mg of gabapentin.3
When dosed 2x daily, Horizant® delivers extended gabapentin exposure1*
- Horizant® provides dose-proportional drug exposure to gabapentin3
*Horizant® for RLS is 600 mg taken once daily with food at about 5 PM. A daily dose of 1200 mg provided no additional benefit compared with the 600 mg dose and caused an increase in adverse reactions.1
24-hour Horizant® concentrations1
For subjects taking Horizant® 600 mg twice daily, the estimated steady-state mean
Cmax was 5.35 μg/mL, Tmax with food was 7.3 hours, mean Cmin was 3.63 μg/mL, and mean peak trough ratio was 1.5.
See how the PROdrug formulation of Horizant® works in the body
AUC=area under the curve; Cmax=maximum concentration; Cmin=minimum concentration; CNS=central nervous system; PK=pharmacokinetic/pharmacokinetics; r2=coefficient of determination; Tmax=time to maximum concentration.
Important Safety Information for HORIZANT® (gabapentin enacarbil) Extended-Release Tablets
INDICATIONS:
HORIZANT® (gabapentin enacarbil) Extended-Release Tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. HORIZANT is not recommended for patients who are required to sleep during the daytime and remain awake at night.
HORIZANT® (gabapentin enacarbil) Extended-Release Tablets are indicated for the management of postherpetic neuralgia (PHN) in adults.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Effects on Driving
HORIZANT may cause significant driving impairment. The duration of driving impairment after starting therapy is unknown. Patients should not drive until they have enough experience on HORIZANT to know if it impairs their driving. Patients’ ability to assess their driving competence and degree of somnolence caused by HORIZANT can be imperfect.
Somnolence/Sedation and Dizziness
HORIZANT causes somnolence/sedation and dizziness. Patients should not drive or operate other complex machinery until they have enough experience on HORIZANT to know if it impairs their ability to perform these tasks.
Lack of Interchangeability with Gabapentin
HORIZANT is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles. The same dose of HORIZANT results in different plasma concentrations of gabapentin relative to other gabapentin products. The safety and effectiveness of HORIZANT in patients with epilepsy have not been studied.
Suicidal Behavior and Ideation
HORIZANT is a prodrug of gabapentin, an antiepileptic drug (AED). AEDs increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. As a prodrug of gabapentin, HORIZANT also increases this risk. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Anyone considering prescribing HORIZANT must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
Patients, caregivers, and families should be informed that HORIZANT increases the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Respiratory Depression
There is evidence from case reports, human studies, and animal studies associating gabapentin with serious, life-threatening, or fatal respiratory depression when co-administered with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe HORIZANT with another CNS depressant, particularly an opioid, or to prescribe HORIZANT to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating HORIZANT at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including HORIZANT).
Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including gabapentin. HORIZANT is a prodrug of gabapentin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. HORIZANT should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Discontinuation of HORIZANT
When discontinuing HORIZANT, patients with RLS receiving 600 mg or less once daily can discontinue the drug without tapering. If the recommended dose is exceeded, the dose should be reduced to 600 mg daily for 1 week prior to discontinuation to minimize the potential of withdrawal seizure.
In patients with PHN receiving HORIZANT twice daily, the dose should be reduced to once daily for 1 week prior to discontinuation to minimize the potential of withdrawal seizure.
Tumorigenic Potential
In an oral carcinogenicity study, gabapentin enacarbil increased the incidence of pancreatic acinar cell adenoma and carcinoma in male and female rats. The clinical significance of this finding is unknown.
ADVERSE REACTIONS
The most common adverse reactions for patients with RLS (incidence >10% and at least 2 times the rate of placebo) were somnolence/sedation and dizziness.
The most common adverse reactions for patients with PHN (incidence >10% and greater than placebo) were dizziness, somnolence, and headache.
DRUG INTERACTIONS
Gabapentin enacarbil is released faster from HORIZANT Extended-Release tablets in the presence of
alcohol. Consumption of alcohol is not recommended when taking HORIZANT.
HORIZANT taken in conjunction with morphine causes increased somnolence/sedation, dizziness, and
nausea.
USE IN SPECIAL POPULATIONS
Pregnancy and Lactation
There are no adequate data on the developmental risk associated with the use of HORIZANT in pregnant women. In nonclinical studies in rats and rabbits, administration of gabapentin enacarbil was developmentally toxic when administered to pregnant animals at doses and gabapentin exposures greater than those used clinically.
It is not known whether gabapentin derived from HORIZANT is secreted in human milk; however, gabapentin is secreted into human milk following oral administration of other gabapentin products. There are no data on the effects of gabapentin on the breastfed infant or the effects on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HORIZANT and any potential adverse effects on the breastfed infant from HORIZANT or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness of HORIZANT in pediatric patients have not been studied.
Geriatric Use
Clinical trials of HORIZANT for the treatment of RLS did not include a sufficient number of patients 65 years and older to determine whether they respond differently from younger individuals. Because elderly patients are more likely to have decreased renal function, the frequency of dosing may need to be adjusted based on calculated creatinine clearance in these patients.
Renal Impairment
Gabapentin is known to be almost exclusively excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. The dose of Horizant should be adjusted in patients with renal impairment based upon creatinine clearance. HORIZANT is not recommended for treatment of RLS in patients receiving hemodialysis.
For additional safety information, please see the complete Prescribing Information for HORIZANT.
To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449, or FDA at 1-800-FDA-1088 or www.fda.gov/MedWatch.
References:
- Horizant [package insert] Woburn, MA: Azurity Pharmaceuticals, Inc.; 2022
- Food and Drug Administration. Orange Book: approved drug products with therapeutic equivalence evaluations [gabapentin enacarbil]. Accessed November 17, 2022. https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm
- Cundy KC, Sastry S, Luo W, et al. Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin. J Clin Pharmacol. 2008;48(12):1378-1388.
- Gralise [prescribing information]. Morristown, NJ: Almatica Pharma LLC.
- Neurontin [prescribing information]. New York, NY: Parke-Davis Division of Pfizer Inc.
- Lal R, Ellenbogen A, Gidal B. Interindividual variability in the bioavailability of gabapentin enacarbil extended release in healthy adults: an analysis of data from 6 phase I studies. Ther Drug Monit. 2022;44(3):448-454.
- Swearingen D, Aronoff GM, Ciric S, et al. Pharmacokinetics of immediate release, extended release, and gastric retentive gabapentin formulations in healthy adults. Int J Clin Pharmacol Ther. 2018;56(5):231-238.
- Yang JY, Lee WI, Shin WK, et al. Administration of four different doses of gabapentin reduces awakening from breakthrough pain and adverse effects in outpatients with neuropathic pain during the initial titration. Korean J Anesthesiol. 2013;65(1):48-54.
- Lee DO, Ziman RB, Perkins AT, et al; XP053 Study Group. A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome. J Clin Sleep Med. 2011;7(3):282-292.
- Walters AS, LeBrocq C, Dhar A, et al; International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4(2):121-132.
- Silber MH, Buchfuhrer MJ, Earley CJ, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clin Proc. 2021;96(7):1921-1937.
- Data on file. Arbor Pharmaceuticals, LLC.
- L, Rainka M, Freeman R, et al. A randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of gabapentin enacarbil in subjects with neuropathic pain associated with postherpetic neuralgia (PXN110748). J Pain. 2013;14(6):590-603.
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