GABAFIX-M

Each capsule contains: Pregabalin IP 75 mg and Methylcobalamin JP 1500 mcg

Each capsule contains: Pregabalin IP 50 mg and Methylcobalamin JP 1500 mcg

Pack Size: 10*10 Blisters

• Neuropathic pain: GABAFIX-M is indicated for the treatment of peripheral and central neuropathic pain in adults.
• Epilepsy: GABAFIX-M is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalization.
• Generalized Anxiety Disorder: GABAFIX-M is indicated for the treatment of Generalized Anxiety Disorder (GAD) in adults.
• Pernicious anemia as a result of in situ B12 deficiency
• Peripheral neuropathies and
• Diabetic polyneuropathy

Pregabalin is removed effectively from plasma by hemodialysis (50% of drug in 4 hours). For patients receiving hemodialysis, the Pregabalin daily dose should be adjusted based on renal function. In addition to the daily dose, a supplementary dose should be given immediately following every 4 hour hemodialysis treatment.

The dosage range for methylcobalamin for clinical effectiveness is 0.5-6 mg/day, and no significant therapeutic advantage is observed beyond this range. However, the most commonly used dose was 0.5 – 1.5 mg/day administered orally.

• Posology: The dose range is 150 to 600 mg per day given in either two or three divided doses.


• Neuropathic Pain: Pregabalin treatment can be started at a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval.


• Epilepsy: Pregabalin treatment can be started with a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week. The maximum dose of 600 mg per day may be achieved after an additional week.


• Following an additional week the dose may be increased to 450 mg per day. The maximum dose of 600 mg per day may be achieved after an additional week.


• Patients with Renal Impairment: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. As pregabalin clearance is directly proportional to creatinine, dose reduction in patients with compromised renal function must be individualized according to creatinine clearance (CLcr), as indicated in Table 1 determined using the following formula:  

  Pregabalin is removed effectively from plasma by hemodialysis (50% of drug in 4 hours). For patients receiving hemodialysis, the Pregabalin daily dose should be adjusted based on renal function. In addition to the daily dose, a supplementary dose should be given immediately following every 4 hour hemodialysis treatment.

  The dosage range for methylcobalamin for clinical effectiveness is 0.5-6 mg/day, and no significant therapeutic advantage is observed beyond this range. However, the most commonly used dose was 0.5 – 1.5 mg/day administered orally.

Table 1. Pregabalin Dose Adjustment Based On Renal Function

Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose

+ Supplementary dose is a single additional dose

• Patients with Hepatic Impairment: No dose adjustment is required for patients with hepatic impairment.
• Elderly (Over 65 Years of Age) Population: Elderly patients may require a dose reduction of pregabalin due to a decreased renal function.

Method of Administration

• GABAFIX-M may be taken with or without food. Pregabalin is for oral use only.

• Hypersensitivity to the active substance or to any of the excipients.
• Known hypersensitivity to B12, or pre-existing hypervitaminosis.
• Known sensitivity to mecobalamin (co-methylcobalamin) or any other ingredient in the preparation
• Known sensitivity to cobalt.
• Megaloblastic anemia of pregnancy without first confirming the diagnosis

• Diabetic Patients: In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycemic medicinal products.


• Hypersensitivity Reactions: Pregabalin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.


• Dizziness, Somnolence, Loss of Consciousness, Confusion, And Mental Impairment: Pregabalin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population.


• Vision-Related Effects: In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than did patients treated with placebo which resolved in a majority of cases with continued dosing.


• Renal failure: Cases of renal failure have been reported and in some cases discontinuation of pregabalin did show reversibility of this adverse reaction.


• Congestive Heart Failure: There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication.


• Treatment of Central Neuropathic Pain Due To Spinal Cord Injury: 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.


• Suicidal Ideation and Behavior: Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents in several indications. Therefore patients should be monitored for signs of suicidal ideation and behaviours and approprsiate treatment should be considered.


• Reduced Lower Gastrointestinal Tract Function: When pregabalin and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and elderly).


• Misuse, Abuse Potential or Dependence: Cases of misuse, abuse and dependence have been reported. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of pregabalin misuse, abuse or dependence (development of tolerance, dose escalation, drug seeking behavior have been reported).


• Encephalopathy: Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.


• Pregnancy: There are no adequate data from the use of pregabalin in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Pregabalin should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the fetus).


• Breast-Feeding: Pregabalin is excreted into human milk. The effect of pregabalin on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue pregabalin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.


• Fertility: There are no clinical data on the effects of pregabalin on female fertility. In a clinical trial to assess the effect of pregabalin on sperm motility, healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment, there were no effects on sperm motility.


• The therapeutic response to vitamin B12 may be impaired by concurrent infection, uremia, folic acid or iron deficiency or by drugs with bone marrow suppressing effects such as chloramphenicol.


• Allergy A sensitivity history should be obtained from the patient prior to administration of vitamin B12.


• An intradermal test dose is recommended before vitamin B12 is administered to patients who may be sensitive to cobalamins. Anaphylactic shock and death have been reported after parenteral vitamin B12 administration.


• Degenerative Lesions of the Spinal Cord Vitamin B12 deficiency that is allowed to progress for longer than 3 months may produce permanent degenerative lesions of the spinal cord.


• The need for vitamin B12 is increased by pregnancy and lactation. the stomach, but this is believed to be related to the underlying pathology and not to treatment with mecobalamin (co-methylcobalamin).

Since GABAFIX-M 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.

• In Vivo Studies and Population Pharmacokinetic Analysis: Accordingly, in in vivo studies no clinically relevant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis indicated that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on pregabalin clearance.


• Oral Contraceptives, Norethisterone and/or Ethinyl Oestradiol: Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either substance.


• CNS Influencing Medical Products: Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, multiple oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. 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.


• Interactions and The Elderly: No specific pharmacodynamics interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.


• Effects on Ability to Drive and Use Machines: Pregabalin may have minor or moderate influence on the ability to drive and use machines. 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 this medicinal product affects their ability to perform these activities.


• Colchicine para-amino salicylic acid and heavy alcohol intake for longer than two weeks may produce malabsorption of vitamin B12


• Serum concentrations of mecobalamin (co-methylcobalamin) may be lowered by oral contraceptives.


• Vitamin B12 concentrations in the blood may be reduced following administration of large and continuous doses of folic acid.


• Folic acid administration may impair the therapeutic response to mecobalamin (co-methylcobalamin).


• The therapeutic response to vitamin B12 may be impaired by drugs with bone marrow suppressing effects such as

In the table below all adverse reactions, which occurred at an incidence greater than placebo and in more than one patient, are listed by class and frequency (very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms have been observed in some patients. The following reactions have been mentioned: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, pain, hyperhidrosis and dizziness, suggestive of physical dependence. The patient should be informed about this at the start of the treatment.

• Methylcobalamine:


• Generalized: Anaphylactic shock and death have been reported with administration of parenteral vitamin B12. Allergic hypersensitivity reactions have rarely occurred.


• Cardiovascular: Pulmonary edema and congestive heart failure early in treatment; peripheral vascular thrombosis. Cardiac arrest, low blood pressure.


• Nervous System: Severe dizziness, drowsiness, muscular paralysis, vision problems, loss of consciousness.


• Hematological: Polycythemia Vera. Hypokalemia.


• Gastrointestinal: Mild transient diarrhea, prolonged abdominal pain, prolonged nausea or vomiting. Dermatological: Itching; transitory exanthema.


• Miscellaneous: Feeling of swelling of entire body bleeding.

Pharmacological Properties

Pharmacodynamics Properties

Pharmacotherapeutic Group: Antiepileptic, other antiepileptic.

Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system. Pharmacodynamics

Pregabalin+Mecobalamin can reduce the release of neurotransmitters and promotes regeneration of neuronal myelin sheath. Pregabalin possess analgesic property and reduce neuropathy-related pain symptoms. Mecobalamin is a cofactor of methionine synthase for the transfer of methyl groups to generate methionine from homocysteine. Elevated level of homocysteine is a predominant risk factor of CAD. Methionine can be converted into s-adenosylmethionine, which involve in methylation reactions related to reduction of depressive disorders.

• Pregabalin selectively binds to voltage-dependent calcium channel and reduce the release of substance P, glutamate, calcitonin-related peptide and norepinephrine. Contrary to other anxiolytics, Pregabalin neither binds to GABA receptors nor increase/influence GABA currents or metabolism.

Pharmacokinetic Properties

Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy receiving anti-epileptic drugs and patients with chronic pain.

• Absorption: 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. Following repeated administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by approximately 25-30% and a delay in tmax to approximately 2.5 hours. However, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin absorption.


• Distribution: In preclinical studies, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. 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.


• Biotransformation: Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin, approximately 98% of the radioactivity recovered in the urine was 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, there was no indication of racemization of pregabalin S -enantiomer to the R-enantiomer.


• Elimination: 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 (see section 5.2 Renal impairment). Dose adjustment in patients with reduced renal function or undergoing hemodialysis is necessary.

Methylcobalamine

• Absorbed vitamin B12 is transported via specific B12 binding proteins, transcobalamin I and II to the various tissues. The liver is the main organ for vitamin B12 storage.


• Within 48 hours after injection of 100 or 1000 micrograms of methylcobalamin, 50 to 98% of the injected dose may appear in the urine. The major portion is excreted within the first eight hours. Intravenous administration results in even more rapid excretion with little opportunity for liver storage.


• Gastrointestinal absorption of vitamin B12 depends on the presence of sufficient intrinsic factor and calcium ions. Intrinsic factor deficiency causes pernicious anemia, which may be associated with sub-acute combined degeneration of the spinal cord. Prompt parenteral administration of vitamin B12 prevents progression of neurologic damage.


• The average diet supplies about 5 to 15 micrograms/day of vitamin B12 in a protein-bound form that is available for absorption after normal digestion. Vitamin B12 is not present in foods of plant origin, but is abundant in foods of animal origin. In people with normal absorption, deficiencies have been reported only in strict vegetarians who consume no products of animal origin (including no milk products or eggs).


• Vitamin B12 is bound to intrinsic factor during transit through the stomach; separation occurs in the terminal ileum in the presence of calcium, and vitamin B12 enters the mucosal cell for absorption. It is then transported by the transcobalamin binding proteins. A small amount (approximately 1% of the total amount ingested) is absorbed by simple diffusion, but this mechanism is adequate only with very large doses. Oral absorption is considered too undependable to rely on in patients with pernicious anemia or other conditions resulting in malabsorption of vitamin B12.

This medicinal product does not require any special storage conditions.