HORIZANT for PHN

Postherpetic neuralgia (PHN) is characterized by acute neuropathic pain, but its symptoms can take various forms, including itching, burning, aching, and sensitivity to touch. The pain and other symptoms of PHN can alter mood, disrupt sleep, and interfere with daily life.1,2

HORIZANT is proven to relieve the pain of postherpetic neuralgia3

  • In the 13-week pivotal trial, HORIZANT 1200 mg (600 mg taken twice daily) reduced 24-hour average pain intensity score by 2.47 points (vs 1.66 points for placebo; P=0.013)
  • More than half (54%) of the patients (n=107) taking HORIZANT 1200 mg had a 30% or greater reduction in their pain intensity score (vs 42% of patients on placebo [n=95])

HORIZANT's innovative PROdrug technology provides 24-hour therapy3,4

  • HORIZANT is dosed twice a day for PHN5
  • HORIZANT has simple, single-step titration to the target dose5

HORIZANT is well tolerated5

  • The most common adverse reactions with HORIZANT 1200 mg (600 mg taken twice daily) were somnolence, dizziness, and headaches
  • Only 6% of patients discontinued treatment due to adverse reactions (vs 13% for placebo)
References
  1. Backonja MM, Canafax DM, Cundy KC. Efficacy of gabapentin enacarbil vs placebo in patients with postherpetic neuralgia and a pharmacokinetic comparison with oral gabapentin. Pain Med. 2011;12:1098-1108.
  2. American Academy of Neurology. AAN Evidence-Based Guideline Summary for Clinicians: Treatment of Postherpetic Neuralgia. St. Paul, MN: American Academy of Neurology; 2004.
  3. Zhang 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.
  4. Cundy KC, Sastry S, Luo W, Zou J, Moors TL, Canafax DM. Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin. J Clin Pharmacol. 2008;48(12):1378-1388.
  5. Horizant [prescribing information]. Santa Clara, CA: XenoPort, Inc; 2013.

Symptoms Reported by RLS Sufferers in the REST Study2

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IRLS Rating Scale Measures a Range of Symptoms1

The IRLS Rating Scale is used to assess the severity of a patient’s RLS symptoms. The patient answers 10 questions in which they rate their symptoms from 0 to 4, with 0 being the absence of symptoms and 4 being very severe. A patient's total score ranges from 0 to 40.

Disease Severity

Mild Moderate Severe Very severe
0 to 10 11 to 20 21 to 30 31 to 40

The 10 questions cover diagnostic symptoms like an urge to move and RLS discomfort as well as associated symptoms like sleep disturbance and impact on daily life. They also cover the severity and frequency of symptoms. The table below shows all 10.

The IRLS Rating Scale was validated in a controlled study and found to have high levels of internal consistency, interexaminer reliability, and test-retest reliability.

Ten Factors of the IRLS Rating Scale

Discomfort in arms or legs

Overall severity of RLS

Need to move because of symptoms

Frequency of symptoms

Movement brings relief

Average severity of symptoms

Severity of sleep disturbance

Impact on daily activities

Severity of sleepiness

Mood disturbance

IRLS Rating Scale Measures a Range of Symptoms3

The IRLS Rating Scale is used to assess the severity of a patient’s RLS symptoms. The patient answers 10 questions in which they rate their symptoms from 0 to 4, with 0 being the absence of symptoms and 4 being very severe. A patient's total score ranges from 0 to 40.

Disease Severity

Mild Moderate Severe Very severe
0 to 10 11 to 20 21 to 30 31 to 40

The 10 questions cover diagnostic symptoms like an urge to move and RLS discomfort as well as associated symptoms like sleep disturbance and impact on daily life. They also cover the severity and frequency of symptoms. The table below shows all 10.

The IRLS Rating Scale was validated in a controlled study and found to have high levels of internal consistency, interexaminer reliability, and test-retest reliability.

Ten Factors of the IRLS Rating Scale

Discomfort in arms or legs

Overall severity of RLS

Need to move because of symptoms

Frequency of symptoms

Movement brings relief

Average severity of symptoms

Severity of sleep disturbance

Impact on daily activities

Severity of sleepiness

Mood disturbance

The CGI-I Scale1

The Clinical Global Impression of Improvement (CGI-I) Scale is a 7-point scale that allows the investigator to rate the patient’s overall change in RLS symptoms from baseline, whether or not in the opinion of the investigator the change is related to study drug treatment.

HORIZANT Pivotal Trial1,2

Design

The efficacy and tolerability of HORIZANT was demonstrated in a 12-week, double-blind, placebo-controlled study in adults diagnosed with primary RLS using the International Restless Legs Syndrome (IRLS) Study Group diagnostic criteria. Patients were randomized to receive HORIZANT 600 mg (N=114), 1200 mg (N=111), or placebo (N=96).

Inclusion criteria

Patients were required to have a score of ≥15 on the IRLS Rating Scale at baseline. Patients with RLS secondary to other conditions (eg, pregnancy, renal failure, iron deficiency anemia) were excluded.

Endpoints

The co-primary endpoints were mean change from baseline in IRLS total score and proportion of responders (rated as “improved” or “very much improved”) on the investigator-rated Clinical Global Impression-Improvement scale (CGI-I) at Week 12 for HORIZANT 1200 mg compared with placebo, last observation carried forward (LOCF). The secondary endpoints included HORIZANT 600 mg compared with placebo on the IRLS and CGI-I at Week 12 LOCF, results from a post-sleep questionnaire, and other subjective sleep measures.

The recommended dosage of HORIZANT for moderate-to-severe primary RLS is 600 mg taken once daily. A daily dose of 1200 mg provided no additional benefit compared with the 600-mg dose and caused an increase in adverse reactions.

HORIZANT PHN Pivotal Trial1,3

Design

This efficacy and tolerability of HORIZANT was demonstrated in a double-blind, placebo-controlled study in adults with postherpetic neuralgia (PHN). The study consisted of a 1-week baseline period, a 1-week up-titration period, a 12-week maintenance treatment period, and a 1-week down-titration period. Patients were randomly assigned to receive HORIZANT 1200 mg/day (n=107), 2400 mg/day (n=82), 3600 mg/day (n=87), or placebo (n=95) and were instructed to take tablets with food.

Inclusion criteria

Patients were required to have a baseline 24-hour average pain score of ≥ 4 on an 11-point pain intensity numerical rating scale (PI-NRS), ranging from 0 (no pain) to 10 (worst possible pain). Average pain scores were calculated using the mean of the daily pain scores for 7 days prior to randomization.

Endpoints

The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score, last observation carried forward. Patients recorded this and other endpoints in an eDiary. Secondary endpoints included the proportion of patients achieving a percent reduction in pain score from baseline and daytime/nighttime worst pain intensity.

The recommended dosage of HORIZANT for PHN is 600 mg twice daily. A daily dose greater than 1200 mg provided no additional benefit but caused an increase in adverse reactions.

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.

CONTRAINDICATION: None.

IMPORTANT SAFETY INFORMATION

Effects on Driving

HORIZANT may cause significant driving impairment. 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 new or worsening 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 new or worsening signs of 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.

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 receiving HORIZANT 600 mg, 1,200 mg, and placebo, respectively, were somnolence/sedation (20%, 27%, and 6%), dizziness (13%, 22%, and 4%), headache (12%, 15%, and 11%), nausea (6%, 7%, and 5%), and fatigue (6%, 7%, and 4%). A daily dose of 1,200 mg provided no additional benefit compared with the 600-mg dose, but caused an increase in adverse reactions.

The most common adverse reactions for patients with PHN taking HORIZANT 1,200 mg and placebo, respectively, were dizziness (17% and 15%), somnolence/sedation (10% and 8%), headache (10% and 9%), nausea (8% and 5%), and fatigue (6% and 1%).

A daily dose greater than 1,200 mg/day provided no additional benefit, but caused an increase in adverse reactions.

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

Based on animal data, HORIZANT may cause fetal harm. There are no adequate and well-controlled studies of HORIZANT in pregnant women. HORIZANT should be used during pregnancy only if potential benefit justifies potential risk to fetus.

HORIZANT is converted to gabapentin, which is secreted into human milk. Discontinue nursing or discontinue HORIZANT, taking into account the importance of HORIZANT to the mother, due to potential for adverse reactions in nursing infants.

Renal Impairment

In patients with RLS who have compromised renal function, HORIZANT should be dosed based upon creatinine clearance (CrCl): 30 to 59 mL/min, start with 300 mg per day and increase to 600 mg as needed; 15 to 29 mL/min, use 300 mg per day; <15 mL/min, use 300 mg every other day. HORIZANT is not recommended for use in patients receiving hemodialysis.

In patients with PHN who have compromised renal function, HORIZANT should be dosed based upon creatinine clearance (CrCl): 30 to 59 mL/min, a titration dose of 300 mg in AM for 3 days, increase to maintenance dose of 300 mg twice daily at Day 4 and increase to 600 mg twice daily as needed, tapering requirement of reduced current maintenance dose to once daily in AM for 1 week; 15 to 29 mL/min, a titration dose of 300 mg in AM on Day 1 and Day 3, use 300 mg in AM as maintenance therapy and increase to 300 mg twice daily if needed, tapering requirement necessary if taking 300 mg twice daily, reduce to 300 mg once daily in AM for 1 week, if taking 300 mg once daily, no tapering needed; <15 mL/min, no titration dose, 300 mg every other day in AM and increase to 300 mg once daily in AM if needed, no tapering needed; <15 mL/min on hemodialysis, no titration dose, 300 mg following every dialysis and increase to 600 mg following every dialysis if needed, no tapering needed.

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