FORMULATION

Each capsule contains:

Pregabalin………75 mg
Methylcobalamin………1500 mcg

DESCRIPTION

Pink (cap)/ White (body) hard gelatin capsules of size “3” containing off-white to light pink colored free flowing powder, with dark red crystals.

PHARMACOLOGICAL PROPERTIES

Pregabalin binds to an auxiliary subunit (α₂-δ protein) of voltage-gated calcium channels in the central nervous system; efficacy has been shown in trials in diabetic neuropathy, post herpetic neuralgia and spinal cord injury.

Methylcobalamin is an essential element in the synthesis of the myelin sheath and in the maintenance of nerve function. The myelin sheath provides insulation to the nerve and aids in the proper and rapid conduction of impulses along the nerve. A deficiency of vitamin B₁₂ results in damage to the myelin sheath

PHARMACOKINETIC PROPERTIES

Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within 1 hour following both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥90% and is independent of dose.  In humans, the apparent volume of distribution of Pregabalin following oral administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins.

Pregabalin undergoes negligible metabolism in humans.  Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.  Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance.

Dose adjustment in patients with reduced renal function or undergoing hemodialysis is necessary.

Methylcobalamin is the neurologically active form of vitamin B12 and occurs as a water-soluble vitamin in the body. Vitamin B12 gets bound to intrinsic factor (IF) and forms a complex. This IF-B12 complex is then absorbed in distal ileum. This absorption is done by a very specific receptor mediated transport system. Vitamin B12 is distributed to different cells of the body upon binding to transcobalamin II. It is stored in the liver. It is a cofactor in the enzyme methionine synthase, which functions to transfer methyl groups for the regeneration of methionine from homocysteine.  It is mainly excreted via urine.

PRECLINICAL SAFETY DATA

In conventional safety pharmacology studies in animals, Pregabalin was well-tolerated at clinically relevant doses. In repeated dose toxicity studies in rats and monkeys CNS effects were observed, including hypoactivity, hyperactivity and ataxia. An increased incidence of retinal atrophy commonly observed in aged albino rats was seen after long term exposure to Pregabalin at exposures ≥ 5 times the mean human exposure at the maximum recommended clinical dose.

Pregabalin was not teratogenic in mice, rats or rabbits. Fetal toxicity in rats and rabbits occurred only at exposures sufficiently above human exposure. In prenatal/postnatal toxicity studies, Pregabalin induced offspring developmental toxicity in rats at exposures > 2 times the maximum recommended human exposure.

Adverse effects on fertility in male and female rats were only observed at exposures sufficiently in excess of therapeutic exposure. Adverse effects on male reproductive organs and sperm parameters were reversible and occurred only at exposures sufficiently in excess of therapeutic exposure or were associated with spontaneous degenerative processes in male reproductive organs in the rat. Therefore the effects were considered of little or no clinical relevance.

Pregabalin is not genotoxic based on results of a battery of in vitro and in vivo tests.

Two-year carcinogenicity studies with Pregabalin were conducted in rats and mice. No tumors were observed in rats at exposures up to 24 times the mean human exposure at the maximum recommended clinical dose of 600 mg/day. In mice, no increased incidence of tumors was found at exposures similar to the mean human exposure, but an increased incidence of hemangiosarcoma was observed at higher exposures. The non-genotoxic mechanism of Pregabalin-induced tumor formation in mice involves platelet changes and associated endothelial cell proliferation. These platelet changes were not present in rats or in humans based on short term and limited long term clinical data. There is no evidence to suggest an associated risk to humans.

In juvenile rats the types of toxicity do not differ qualitatively from those observed in adult rats. However, juvenile rats are more sensitive. At therapeutic exposures, there was evidence of CNS clinical signs of hyperactivity and bruxism and some changes in growth (transient body weight gain suppression). Effects on the estrus cycle were observed at 5-fold the human therapeutic exposure. Reduced acoustic startle response was observed in juvenile rats 1-2 weeks after exposure at > 2 times the human therapeutic exposure. Nine weeks after exposure, this effect was no longer observable.

There are no pre-clinical data of relevance on Methylcobalamin which are additional to that already included in other sections of the SPC.

INDICATIONS

Indicated for the treatment of neuropathic pain in patients with diabetic peripheral neuropathy and post herpetic neuralgia.

CONTRAINDICATION

Contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.

DOSAGE AND ADMINISTRATION

Recommended adult dose is one tablet once or twice daily. Or as prescribed by the physician.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. As Pregabalin clearance is directly proportional to creatinine clearance, dose reduction in patients with compromised renal function must be individualized according to creatinine clearance.  Some diabetic patients who gain weight on Pregabalin treatment may need to adjust hypoglycemic medicinal products.

Pregabalin should be discontinued immediately if symptoms of hypersensitivity such as angioedema, such as facial, perioral, or upper airway swelling occur.  Pregabalin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medicinal product.

Pregabalin may cause blurred vision in some patients.  Discontinuation of Pregabalin may result in resolution or improvement of these visual symptoms.

In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, central nervous system adverse reactions and especially somnolence was increased. This may be attributed to an additive effect due to concomitant medicinal products (e.g. anti-spasticity agents) needed for this condition. This should be considered when prescribing Pregabalin in this condition.

Dose adjustment in patients with reduced renal function or undergoing hemodialysis is necessary.

Vitamin B₁₂ supplementation can mask folate deficiency. In such patients, folate supplementation may be needed.

USE DURING PREGNANCY AND LACTATION

Safety and efficacy have not been evaluated in pregnancy and lactation hence Pregabalin + Methylcobalamin should not be given to pregnant and lactating women.

PEDIATRIC USE

Safety of Pregabalin + Methylcobalamin has not been established in children.

DRUG INTERACTIONS

Since Pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (< 2% of a dose recovered in urine as metabolites), does not inhibit drug metabolism in vitro, and is not bound to plasma proteins, it is unlikely to produce, or be subject to, pharmacokinetic interactions.

Pregabalin may potentiate the effects of ethanol and lorazepam. In the post-marketing experience, there are reports of respiratory failure and coma in patients taking Pregabalin and other CNS depressant medicinal products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.

ADVERSE EFFECTS

The most commonly reported adverse reactions with Pregabalin are dizziness and somnolence. Adverse reactions are usually mild to moderate in intensity. Hypersensitivity, increase in appetite, euphoric mood, confusion, irritability, disorientation, insomnia may occur. Methylcobalamin may rarely cause itching and allergic reactions.

EFFECTS ON ABILITY TO DRIVE

Pregabalin may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether Pregabalin + Methylcobalamin capsule affects their ability to perform these activities.

OVERDOSAGE

The most commonly reported symptoms observed with Pregabalin overdose included somnolence, confusional state, agitation, and restlessness.  In rare occasions, cases of coma have been reported.

Treatment of overdose should include general supportive measures and may include hemodialysis if necessary.

CAUTION

Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without a prescription.

STORE AT TEMPERATURES NOT EXCEEDING 30^OC.

AVAILABILITY

75 mg / 1500 mcg X Alu-Alu blister pack of 10’s; box of 30 capsules

FOR SUSPECTED ADVERSE DRUG REACTION, REPORT TO THE FDA: www.fda.gov.ph  

Seek medical attention immediately at the first sign of any adverse drug reaction.

NUROGESIC B^® is a registered trademark of Ajanata Pharma Philippines, Inc.

Registration No.: DR-XY46624