Neugaba

                                                                                                         

COMPOSITION

Each  Capsule contains;                         

Pregabalin……………75mg/150mg

                  

DESCRIPTION
Pregabalin  is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults.It has also been found effective for generalized anxiety disorder and is (as of 2007) approved for this use in the European Union. It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade name Lyrica. Pfizer described in an SEC filing that the drug could be used to treat epilepsy, post-herpetic neuralgia, diabetic peripheral neuropathy and fibromyalgia. Sales reached a record $3.063 billion in 2010.
Recent studies have shown that pregabalin is effective at treating chronic pain in disorders such as fibromyalgia and spinal cord injury. In June 2007, pregabalin became the first medication approved by the U.S. Food and Drug Administration specifically for the treatment of fibromyalgia.
It is considered to have a low potential for abuse, and a limited dependence liability if misused, but is classified as a Schedule V drug in the U.S.

The IUPAC chemical name for pregabalin is (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid. Its chemical formula is C₈H₁₇NO₂ giving it a molecular mass of

159.23 g/mol. It is both an amine and a carboxylic acid.

PHARMACODYNAMIC

MECHANISM OF ACTION; Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the alpha₂–delta (α₂–δ) protein, an auxiliary subunit of voltage-gated calcium channels.

 Pregabalin binds potently and selectively to the alpha-2-delta subunit of “hyper-excited” voltage-gated calcium channels (VGCCs). The binding of pregabalin to VGCCs changes their conformation, reducing calcium influx at nerve terminals. Pregabalin only modulates the release of excitatory neurotransmitters in “hyper-excited” neurons, restoring them to normal physiological state. This newly defined MOA is believed to confer on pregabalin its anxiolytic, analgesic, and anticonvulsant properties. Thus, pregabalin may offer physicians an effective and well-tolerated therapy for GAD, which differs from existing treatments.

PHARMACOKINETICS ]

Absorption and Distribution

Following oral administration of NEUGABA capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is ≥90% and is independent of dose. Following single- (25 to 300 mg) and multiple- dose (75 to 900 mg/day) administration, maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.

The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in Cmax of approximately 25% to 30% and an increase in Tmax to approximately 3 hours. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.

Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.

Metabolism and Elimination

Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (S- enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to creatinine clearance (CLcr).

Pharmacokinetics in Special Populations

Race

In population pharmacokinetic analyses of the clinical studies in various populations, the pharmacokinetics of Pregabalin were not significantly affected by race (Caucasians, Blacks, and Hispanics).

Gender

Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and Pregabalin drug exposure is similar between genders.

Renal Impairment and Hemodialysis

Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, dosing must be modified.

Elderly

Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.

Pediatric Pharmacokinetics

Pharmacokinetics of pregabalin have not been adequately studied in pediatric patients

Drug Interactions

In Vitro Studies

Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g. theophylline, caffeine) or CYP 3A4 substrates (e.g. midazolam, testosterone) is not anticipated.

In Vivo Studies

The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.

Gabapentin

The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every 8 hours and 400-mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin coadministration. The extent of pregabalin absorption was unaffected by gabapentin coadministration, although there was a small reduction in rate of absorption.

Oral Contraceptive

Pregabalin coadministration (200 mg three times a day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 µg, respectively) in healthy subjects.

Lorazepam

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam (1 mg) had no effect on the steady-state pharmacokinetics of pregabalin.

Oxycodone

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no effect on the steady-state pharmacokinetics of pregabalin.

Ethanol

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0.7 g/kg) had no effect on the steady-state pharmacokinetics of pregabalin.

Phenytoin, carbamazepine, valproic acid, and lamotrigine

Steady-state trough plasma concentrations of phenytoin, carbamazepine and carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg three times a day) administration.

Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant medications suggest the following:

Therapeutic class Specific concomitant drug studied

Concomitant drug has no effect on the pharmacokinetics of pregabalin

Hypoglycemics	Glyburide, insulin, metformin
Diuretics	Furosemide
Antiepileptic Drugs	Tiagabine

Concomitant drug has no effect on the pharmacokinetics of pregabalin and pregabalin has no effect on the pharmacokinetics of concomitant drug

Therapeutic class	Specific concomitant drug studied
Antiepileptic Drugs	Carbamazepine, lamotrigine, phenobarbital,
	phenytoin, topiramate, valproic acid

PHARMACOKINETIC PROPERTY	PREGABALIN	GABAPENTIN
Absorption time to Cmax (hr)	1.5	1.5-4
Bioavailability	≥90%	27%-60%
Effect of food on absorption	↓ rate ,↔ extent	14% ↑se in AUC& Cmax
Protein binding	Negligible	3%
Metabolism	None	None
Elimination	Renal	Renal
Half-life(Hrs)	6.3	5-7
Dose concentration relationship	Proportionl	Dispropionate
t max(Hrs)	1	2-3
Potency	++++++	+
Controlled substance	Schedule V	NO
Neuropathic pain dose	150-600mg/day	1800-3600mg/day
Time to effective dose	1 day	9 days

INDICATIONS AND DOSAGE;

Management of neuropathic pain associated with

Ø  Diabetic Peripheral Neuropathy;

Ø  Postherpetic neuralgia .

Adjunctive therapy for adults with partial-onset seizures;

Management of fibromyalgia.

UNLABELLED USES

Treatment of generalized anxiety disorder.

DOSAGE AND ADMINISTRATION

Neuropathic Pain Associated With Diabetic Peripheral Neuropathy
Adults

PO 50 mg 3 times daily initially, increased to 100 mg 3 times daily within 1 wk based on efficacy and tolerability (max, 300 mg/day).

Partial-Onset Seizures
Adults

PO 75 mg twice daily or 50 mg 3 times daily initially, increased to 150 to 600 mg/day divided 2 or 3 times daily based on efficacy and tolerability (max, 600 mg/day).

Postherpetic Neuralgia
Adults

PO 75 mg twice daily or 50 mg 3 times daily initially, increased to 150 mg twice daily or 100 mg 3 times daily within 1 wk based on efficacy and tolerability. If relief is insufficient after 2 to 4 wk, may increase up to 300 mg twice daily or 200 mg 3 times daily.

Fibromyalgia
Adults

PO 75 mg twice daily initially, increased to 150 mg twice daily within 1 wk based on efficacy and tolerability. Patients not experiencing sufficient benefit may further increase the dosage to 225 mg twice daily (max, 450 mg/day).

Dosage Adjustment for Renal Function Impairment
Adults

CrCl 60 mL/min or greater: total daily dose range of 150 to 600 mg/day administered twice daily or 3 times daily; CrCl 30 to 60 mL/min: total daily dose range of 75 to 300 mg/day administered twice daily or 3 times daily; CrCl 15 to 30 mL/min: total daily dose range of 25 to 150 mg administered once or twice daily; CrCl less than 15 mL/min: total daily dose range of 25 to 75 mg/day administered once daily.

Hemodialysis patients

Maintenance doses based on CrCl as recommended plus a supplemental posthemodialysis dose administered after each 4 h of hemodialysis as follows: if maintenance dose 25 mg once daily, postdialysis dose is 25 or 50 mg; if maintenance dose is 25 to 50 mg once daily, postdialysis dose is 50 or 75 mg; if maintenance dose is 50 to 75 mg once daily, postdialysis dose is 75 or 100 mg; if maintenance dose is 75 mg daily, postdialysis dose is 100 to 150 mg.

General Advice

• May be given with or without food.
• When discontinuing, taper gradually over a minimum of 1 wk.

CONTRA-INDICATIONS

Hypersensitivity to Pregabalin or any of the other product components.

PRECAUTION AND WARNING;

Precautions

Monitor Monitor for emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in behavior. Monitor for weight gain and/or fluid retention, possibly exacerbating or leading to heart failure. Carefully evaluate patients for a history of drug abuse and observe them for signs of pregabalin misuse or abuse (eg, development of tolerance, dose escalation, drug-seeking behavior).

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Because of age-related renal function impairment, dosage adjustment may be needed.

Hypersensitivity

Hypersensitivity reactions (including skin redness, blisters, hives, rash, dyspnea, and wheezing) have been reported shortly after initiation of pregabalin.

Renal Function

Dose reduction recommended.

Hazardous Tasks

May cause dizziness and drowsiness, which may impair the ability to preform tasks such as driving or operating machinery.

Angioedema

Has been reported during initial and long-term treatment.

CHF

Use with caution in patients with New York Heart Association class III or IV cardiac status.

Creatine kinase elevations

Have been reported. Discontinue pregabalin if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.

Decreased platelet count

Clinically significant decreases in platelets (20% below baseline and less than 150 × 10 ³ /mcL) have been documented.

Dependence

Withdrawal symptoms may occur suggestive of physical dependence.

Discontinuation of therapy

Withdraw gradually (over at least 1 wk) to minimize potential of increased seizure frequency in patients with seizure disorders. Upon abrupt or rapid discontinuation, insomnia, nausea, headache, and diarrhea have been reported.

Ophthalmic effects

Reduction in visual acuity, visual field changes, and funduscopic changes have been reported.

Peripheral edema

Has been reported. Occurs more frequently in patients taking pregabalin and a thiazolidinedione antidiabetic agent.

PR interval prolongation

PR interval prolongation (3 to 6 msec) has been reported; the mean change difference was not associated with an increased risk of PR increase more than 25% from baseline, on-treatment PR more than 200 msec, or increased risk of second- or third-degree AV block.

Suicidal behavior and ideation

May increase the risk of suicidal thoughts or behavior. This was observed as early as 1 week after starting treatment and persisted for the duration of treatment.

Weight gain

Has been reported.

Overdosage

Symptoms

None well documented.

ADVERSE REACTION

CNS

Dizziness (45%); somnolence (28%); ataxia (20%); headache (14%); tremor (11%); abnormal thinking, balance disorder, neuropathy (9%); abnormal gait, fatigue (8%); asthenia, confusion, euphoria, speech disorder (7%); amnesia, disturbances in attention, incoordination (6%); twitching (5%); memory impairment, myoclonus, vertigo (4%); abnormal feeling, hypesthesia (3%); anxiety, depression, disorientation, drunk feeling, lethargy (2%); depersonalization, hypertonia, paresthesia, stupor (at least 1%); nervousness (1%).

Eye & ENT

Blurred vision, diplopia (12%); abnormal vision (5%); pharyngolaryngeal pain (3%); eye disorder (2%); conjunctivitis, nystagmus, otitis media, tinnitus (at least 1%).

GI

Dry mouth (15%); constipation (10%); increased appetite (7%); flatulence, vomiting (3%); abdominal distension (2%); abdominal pain, gastroenteritis (at least 1%); diarrhea, nausea (postmarketing).

Genitourinary

Urinary incontinence (2%); anorgasmia, impotence, libido decreased, urinary frequency (at least 1%).

Metabolic-Nutritional

Peripheral edema, weight gain (16%); edema (6%); face edema, fluid retention, hypoglycemia (3%).

Musculoskeletal

Arthralgia (6%); back pain, muscle spasm (4%); leg cramps, myalgia, myasthenia (at least 1%).

Respiratory

Sinusitis (7%); bronchitis, dyspnea (3%).

Miscellaneous

Infection (14%); pain (5%); chest pain (4%); flu syndrome (2%); allergic reaction, ecchymosis, fever, pruritus (at least 1%); angioedema, hypersensitivity (postmarketing).

STORAGE AND HANDLING INSTRUCTIONS

Store in a cool dry place, protect from light.

PRESENTATION:

NEUGABA is available in a blister of 10 Tablets.

Each box of NEUGABA contains 5 X 10’s