Gralise Dailymed

1 Indications And Usage

GRALISE is indicated for the management of postherpetic neuralgia.

GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.


GRALISE is indicated for the management of Postherpetic Neuralgia (PHN).

Important Limitation: GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration (See Warnings and Precautions)

2 Dosage And Administration

• GRALISE should be titrated to an 1,800 mg dose taken orally, once-daily, with the evening meal. GRALISE tablets should be swallowed whole. Do not crush, split, or chew the tablets. (2.1)
• If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). (2.1)
• Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used in patients with CrCl less than 30 or in patients on hemodialysis. (2.2)

2.1 Postherpetic Neuralgia

Do not use GRALISE interchangeably with other gabapentin products.

Titrate GRALISE to an 1,800 mg dose taken orally once daily with the evening meal. GRALISE tablets should be swallowed whole. Do not split, crush, or chew the tablets.

If GRALISE dosing is reduced, discontinued, or substituted with an alternative medication, this should be done gradually over a minimum of one week or longer (at the discretion of the prescriber).

In adults with postherpetic neuralgia, GRALISE therapy should be initiated and titrated as follows:

Table 1: GRALISE Recommended Titration Schedule

	Day 1	Day 2	Days 3-6	Days 7-10	Days 11-14	Day 15
Daily Dose	300 mg	600 mg	900 mg	1,200 mg	1,500 mg	1,800 mg

2.2 Patients with Renal Impairment

In patients with stable renal function, creatinine clearance (C_Cr) can be reasonably well estimated using the equation of Cockcroft and Gault:          For females C_Cr=(0.85)(140-age)(weight)/[(72)(S_Cr)]          For males C_Cr=(140-age)(weight)/[(72)(S_Cr)]where age is in years, weight is in kilograms and S_Cr is serum creatinine in mg/dL.

The dose of GRALISE should be adjusted in patients with reduced renal function, according to Table 2. Patients with reduced renal function must initiate GRALISE at a daily dose of 300 mg. GRALISE should be titrated following the schedule outlined in Table 1. Daily dosing in patients with reduced renal function must be individualized based on tolerability and desired clinical benefit.

Table 2: GRALISE Dosage Based on Renal Function

Once-daily dosing
Creatinine Clearance (mL/min)	GRALISE Dose (once daily with evening meal)
≥ 60	1,800 mg
30 - 60	600 mg to 1,800 mg
< 30	GRALISE should not be administered
patients receiving hemodialysis	GRALISE should not be administered

3 Dosage Forms And Strengths

Tablets:

• 300 mg, white, oval, debossed with “SLV” on one side and “300” on the other side.
• 450 mg, red, oval, debossed with “ALM” on one side and “450” on the other side.
• 600 mg, beige, oval, debossed with “SLV” on one side and “600” on the other side.
• 750 mg, yellow, oval, debossed with “ALM” on one side and “750” on the other side.
• 900 mg, pink, oval, debossed with “ALM” on one side and “900” on the other side.

• Tablets: 300 mg, 450 mg, 600 mg, 750 mg, and 900 mg (3)

4 Contraindications

GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients.


GRALISE is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. (4)

5 Warnings And Precautions

GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

The safety and effectiveness of GRALISE in patients with epilepsy has not been studied.

• GRALISE is not interchangeable with other gabapentin products
• Antiepileptic drugs, including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior (5.1)
• Respiratory depression may occur with GRALISE when used with concomitant CNS depressants or in the setting of underlying respiratory impairment. Monitor patients and adjust dosage as appropriate. (5.2)
• Increased seizure frequency may occur in patients with seizure disorders if GRALISE is rapidly discontinued. Withdraw GRALISE gradually over a minimum of 1 week. (5.3)

5.1 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. 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.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs.

Table 3: Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in GRALISE) in the Pooled Analysis

Indication	Placebo Patients with Events Per 1,000 Patients	Drug Patients with Events Per 1,000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1,000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that GRALISE contains gabapentin which is also used to treat epilepsy and that AEDs increase 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 about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

5.2 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-administrated with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe GRALISE with another CNS depressant, particularly an opioid, or to prescribe GRALISE to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating GRALISE at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including GRALISE).

5.3 Withdrawal of Gabapentin

Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber).

5.4 Tumorigenic Potential

In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown.

In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients, and pre-existing tumors worsened in 11 patients, during or within 2 years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown.

5.5 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 GRALISE. 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. GRALISE should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.6 Laboratory Tests

Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not been established.

6 Adverse Reactions

• The most common adverse reaction (greater than or equal to 5% and twice placebo) is dizziness. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Almatica Pharma LLC at 1-877-447-7979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

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 practice.

A total of 359 patients with neuropathic pain associated with postherpetic neuralgia have received GRALISE at doses up to 1,800 mg daily during placebo-controlled clinical studies. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE treatment group, the most common reason for discontinuation due to adverse reactions was dizziness. Of GRALISE-treated patients who experienced adverse reactions in clinical studies, the majority of those adverse reactions were either "mild" or "moderate".

Table 4 uls all adverse reactions, regardless of causality, occurring in at least 1% of patients with neuropathic pain associated with postherpetic neuralgia in the GRALISE group for which the incidence was greater than in the placebo group.

Table 4: Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and More Frequent Than in the Placebo Group)

Body System - Preferred Term	GRALISEN = 359%	PlaceboN = 364%
Ear and Labyrinth Disorders
Vertigo	1.4	0.5
Gastrointestinal Disorders
Diarrhea	3.3	2.7
Dry mouth	2.8	1.4
Constipation	1.4	0.3
Dyspepsia	1.4	0.8
General Disorders
Peripheral edema	3.9	0.3
Pain	1.1	0.5
Infections and Infestations
Nasopharyngitis	2.5	2.2
Urinary tract infection	1.7	0.5
Investigations
Weight increased	1.9	0.5
Musculoskeletal and Connective Tissue Disorders
Pain in extremity	1.9	0.5
Back pain	1.7	1.1
Nervous System Disorders
Dizziness	10.9	2.2
Somnolence	4.5	2.7
Headache	4.2	4.1
Lethargy	1.1	0.3

In addition to the adverse reactions reported in Table 4 above, the following adverse reactions with an uncertain relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection.

6.2 Postmarketing and Other Experience with other Formulations of Gabapentin

In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been uled above and data are insufficient to support an estimate of their incidence or to establish causation. The uling is alphabetized: angioedema, blood glucose fluctuation, breast enlargement, bullous pemphigoid, elevated creatine kinase, elevated liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome.

Adverse events following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating.

There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking gabapentin with opioids or other central nervous system (CNS) depressants, or in the setting of underlying respiratory impairment.

12.1 Mechanism of Action

The mechanism of action by which gabapentin exerts its analgesic action is unknown but in animal models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). Gabapentin prevents pain-related responses in several models of neuropathic pain in rats and mice (e.g., spinal nerve ligation models, spinal cord injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formulin test), but does not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase). The relevance of these models to human pain is not known.

Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid), but it does not modify GABA_A or GABA_B radioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. In radioligand binding assays at concentrations up to 100 μM, gabapentin did not exhibit affinity for a number of other receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or strychnine-sensitive glycine; alpha 1, alpha 2, or beta adrenergic; adenosine A1 or A2; cholinergic, muscarinic, or nicotinic; dopamine D1 or D2; histamine H1; serotonin S1 or S2; opiate mu, delta, or kappa; cannabinoid 1; voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem; or at voltage-sensitive sodium channel sites labeled with batrachotoxinin A20-alpha-benzoate. Gabapentin did not alter the cellular uptake of dopamine, noradrenaline, or serotonin.

In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain tissue has been identified as an auxiliary subunit of voltage-activated calcium channels. However, functional correlates of gabapentin binding, if any, remain to be elucidated. It is hypothesized that gabapentin antagonizes thrombospondin binding to α2δ-1 as a receptor involved in excitatory synapse formation and suggested that gabapentin may function therapeutically by blocking new synapse formation.

12.2 Pharmacodynamics

No pharmacodynamic studies have been conducted with GRALISE.

12.3 Pharmacokinetics

Absorption

Gabapentin is absorbed from the proximal small bowel by a saturable L-amino transport system. Gabapentin bioavailability is not dose proportional; as the dose is increased, bioavailability decreases.

When GRALISE (1,800 mg once daily) and gabapentin immediate release (600 mg three times a day) were administered with high fat meals (50% of calories from fat), GRALISE has a higher C_max and lower AUC at steady state compared to gabapentin immediate release (Table 5). Time to reach maximum plasma concentration (T_max) for GRALISE is 8 hours, which is about 4-6 hours longer compared to gabapentin immediate release.

Table 5: Mean ± SD Steady-State Pharmacokinetics for GRALISE and Gabapentin Immediate Release in Healthy Subjects under high-fat high calorie fed state (Day 5, n = 21)

PharmacokineticParameter(Mean ± SD)	GRALISE1,800 mg QD (3 x 600 mg)	Gabapentin Immediate Release600 mg TID
$Tmax is presented as median (range); * relative to most recent dose
AUC0-24 (μg.hr/mL)	132.8 ± 34.7	141.3 ± 29.8
Cmax (μg/mL)	9.59 ± 2.33	8.54 ± 1.72
Cmin (μg/mL)	1.84 ± 0.65	2.6 ± 0.78
Tmax (hr) $	8 (3-12)	2 (1-5)*

The single dose pharmacokinetic parameters of 900 mg strength under high fat-high calorie fed state and low fat-low calorie fed state are presented shown in Table 6.

Table 6: Mean ± SD Single-Dose Pharmacokinetic parameters for GRALISE 900 mg strength in Healthy Subjects (n = 27)

$Tmax is presented as median (range)
Pharmacokinetic Parameter (Mean ± SD)	GRALISE 1,800 mg (2 x 900 mg tablets)
	High fat- high calorie fed state	Low fat- low calorie fed state
Cmax (μg/mL)	9.49 ± 1.93	6.50 ± 2.16
AUCt (μg.hr/mL)	127.2 ± 42.8	79.1 ± 39.4
AUCinf (μg.hr/mL)	133.2 ± 43.2	84.8 ± 39.4
Tmax (hr)$	7 (4-12)	4 (3-12)

Do not use GRALISE interchangeably with other gabapentin products because of differing pharmacokinetic profiles that affect frequency of administration.

GRALISE should be taken with evening meals. If it is taken on an empty stomach, the bioavailability will be substantially lower.

Administration of GRALISE with food increases the rate and extent of absorption of gabapentin compared to the fasted state. C_max of gabapentin increases 33-84% and AUC of gabapentin increases 33-118% with food depending on the fat content of the meal. GRALISE should be taken with food.

Distribution

Gabapentin is less than 3% bound to plasma proteins. After 150 mg intravenous administration, the mean ± SD volume of distribution is 58 ± 6 L.

Elimination

Gabapentin is eliminated by renal excretion as unchanged drug.

In patients with normal renal function given gabapentin immediate release 1,200 to 3,000 mg/day, the drug elimination half-life (t_1/2) was 5 to 7 hours. Elimination kinetics do not change with dose level or multiple doses.

Metabolism

Gabapentin is not appreciably metabolized in humans.

Excretion

Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients and patients with impaired renal function, plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.

Dosage adjustment in patients with compromised renal function is necessary. In patients undergoing hemodialysis, GRALISE should not be administered [see Dosage and Administration (2.2)].

12.4 Special Populations

Renal Insufficiency:  As renal function decreases, renal and plasma clearances and the apparent elimination rate constant decrease, while C_max and t_1/2 increase.

In patients (N=60) with creatinine clearance of at least 60, 30 to 59, or less than 30 mL/min, the median renal clearance rates for a 400 mg single dose of gabapentin immediate release were 79, 36, and 11 mL/min, respectively, and the median t_1/2 values were 9.2, 14, and 40 hours, respectively.

Dosage adjustment is necessary in patients with impaired renal function [see Dosage and Administration (2.2)].

Hemodialysis:  In a study in anuric adult subjects (N=11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects. GRALISE should not be administered in patients undergoing hemodialysis. Alternative formulations of gabapentin products should be considered in patients undergoing hemodialysis.

Elderly:  Apparent oral and renal clearances of gabapentin decrease with increasing age, although this may be related to the decline in renal function with age. Reductions in gabapentin dose should be made in patients with age-related compromised renal function [see Dosage and Administration (2.2)].

Hepatic Impairment:  Because gabapentin is not metabolized, studies have not been conducted in patients with hepatic impairment.

Pediatrics:  The pharmacokinetics of GRALISE have not been studied in patients less than 18 years of age.

Gender:  Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences.

Race:  Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.