Funxion Plus

Pregabalin, mecobalamin.

Each capsule contains: Pregabalin 75 mg, Mecobalamin 750 mcg.

Pharmacology: Pharmacodynamics: Pregabalin: Pregabalin is an anticonvulsant that is structurally related to the inhibitory central nervous system (CNS) neurotransmitter gamma aminobutyric acid (GABA). Although pregabalin was developed as a structural analog of GABA, the drug does not bind directly to GABA_A, GABA_B, or benzodiazepine receptors; does not augment GABA_A responses in cultured neurons; and does not alter brain concentrations of GABA in rats or affect GABA uptake or degradation. However, in cultured neurons, prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport.
Pregabalin binds with high affinity to the α₂-δ site (an auxiliary subunit of voltage-gated calcium channels) in CNS tissues. Although the exact mechanism of action of pregabalin has not been elucidated, binding to the α₂-δ subunit may be involved in pregabalin's anticonvulsant effect.
Mecobalamin: Mecobalamin is an active form of Vitamin B₁₂. It regenerates damaged neuron by serving as a cofactor in the methionine synthase reaction. Mecobalamin transfers its methyl group to homocysteine to yield methionine. Methionine is a precursor of S-adenosylmethionine (SAMe), the principal transmethylating agent in the body. SAMe is also involved in the synthesis of myelin basic protein. Thus, mecobalamin helps in maintaining the integrity of the myelin sheath, the protective coating that surrounds the nerve fibers.
Pharmacokinetics: Pregabalin: Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within one hour after both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥90% and is independent of dose. Maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) values increase proportionally after single- and multiple-dose administration. After 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 C_max by approximately 25 to 30% and a delay in T_max to approximately 2.5 hours. However, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin bioavailability.
At clinical doses of 150 to 600 mg per day, the average steady-state plasma pregabalin concentrations were approximately 1.5 and 6 mcg/mL, respectively. Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (< 20%). Multiple dose pharmacokinetics are predictable from single-dose data.
The apparent volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin is not bound to plasma proteins. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. In animal models, pregabalin has been shown to cross the blood brain barrier.
Pregabalin undergoes negligible metabolism in human. After 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.
In vitro drug metabolism showed that pregabalin, at concentrations which were generally 10-fold greater than observed in Phase 2/3 clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2D6, CYP2E1, and CYP3A4 enzyme systems.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Renal clearance (CL_cr) derived from Phase I studies was 73 mL/min. Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance.
Special Population: Renal impairment: Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (after a four-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is the major elimination pathway, dosage reduction in patients with renal impairment and dosage supplementation after hemodialysis is necessary.
Hepatic impairment: Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.
Elderly: Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decreases in creatinine clearance associated with increasing age. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
Mecobalamin: Vitamin B₁₂ is a collective term for all cobalt-containing, bioactive members of the cobalamin family. The principal cobalamins are cyanocobalamin, hydroxocobalamin and the other two coenzyme forms of vitamin B₁₂, which are mecobalamin and 5-deoxyadenosylcobalamin (adenosylcobalamin). Vitamin B₁₂ binds and forms a complex with R protein (also known as haptocorrin), a protein secreted by the salivary glands and gastric mucosa that may protect vitamin B₁₂ as it travels through the stomach and into the small intestine. Haptocorrins have high affinity for vitamin B₁₂ in acidic condition; thus, binding occurs in the stomach. B₁₂-haptocorrin complexes are partially degraded by pancreatic proteases through hydrolysis in the small intestine in order to release B₁₂. The released B₁₂ will bind to intrinsic factor (IF), a 45-kDa glycoprotein secreted by the gastric parietal cells. Sufficient IF is released following a meal to bind two to four micrograms of vitamin B₁₂.
Absorption of vitamin B₁₂ occurs via two mechanisms: passive diffusion and active or physiological absorption. Passive diffusion occurs throughout the gastrointestinal tract. About one percent of any given dose of vitamin B₁₂ is absorbed through this mechanism. On the other hand, active or physiological absorption occurs when the B₁₂-IF complex is absorbed via a 460-kDa receptor called cubilin located in the distal ileum of the small intestine. Cubilin reacts with a second protein called amnionless (AMN), which is needed for the apical localization of cubilin in polarized cells. The B₁₂-IF complex binds to cubilin in the presence of Ca²⁺ and the internalized in the late endosomes through receptor-mediated endocytosis. The late endosomes then fuse with lysosomes resulting to the degradation of IF and the release of the vitamin B₁₂ into the cytosol. The released vitamin B₁₂ traverses the endothelial cell and enters the portal circulation. The process of vitamin B₁₂ absorption across the gut epithelium takes about three to four hours. The refractory period to restore unbound cubilin density and the maximal absorptive capacity is about six hours.
The physiological absorption mechanism can become saturated with relatively small amounts of oral vitamin B₁₂; thus, increased vitamin B₁₂ intake increases its total absorption, but the absorption efficiency of the vitamin decreases with increased dosage. About 50% of a vitamin B will be absorbed for doses of three micrograms or less, while percent absorption gradually decreases for doses greater than three micrograms. The maximum amount that can be absorbed from a given dose of vitamin B is approximately 1.5 mcg.
Vitamin B₁₂ absorption can be impaired by the following: absence or removal of the ileum or stomach, overgrowth of bacteria in the stomach, infestation with the tapeworm Diphyllobothrium latum, reduction of gastric acid production due to prolonged use of gastric acid inhibitors, malabsorption syndrome, disease or abnormality of the gut, atrophic gastritis or the lack of R protein, pancreatic enzymes or IF.
Recent evidences suggest that the released vitamin B₁₂ exits the enterocyte via the multidrug resistance protein 1 (MRP1/ABCC1) before forming a complex with transcobalamin in the blood. Transcobalamin is a 45.5 kDa β-globulin protein synthesized in the endothelial cells, enterocytes, liver and macrophages. The transcobalamin-vitamin B₁₂ complex is taken up in the tissues via receptor-mediated endocytosis. Transcobalamin delivers vitamin B₁₂ to the portal circulation and eventually to the liver, where 50% of the vitamin is taken up and stored. The remainder goes to the systemic circulation to be transported to the other tissues of the body.
The transcobalamin-vitamin B₁₂ complex is intracellularly degraded by lysosomal proteases to yield hydroxycob(III)alamin. In the cytosol, hydroxycob(III)alamin is reduced to cob(I)alamin, which is then methylated to the methylcob(III)alamin after binding to methionine synthase. Mecobalamin is the principal circulating form of vitamin B₁₂.
Vitamin B₁₂ is excreted in the bile. Its reabsorption via enterohepatic circulation requires the IF. Some of the B₁₂ secreted in the bile and unabsorbed oral B₁₂ is excreted in the feces. A small fraction of the dose is excreted in the urine, most of it in the first eight hours.

For the management of peripheral neuropathy.

Recommended dose: One capsule twice a day.
Patients with Renal Impairment: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Since pregabalin clearance is directly proportional to creatinine clearance, dosage reduction in patients with compromised renal function should be individualized according to the creatinine clearance (CrCl) to be determined using the Cockroft-Gault formula. Patients previously on gabapentin should have a wash-out period of one week prior to start dosing with pregabalin.
Pregabalin is effectively removed from plasma by hemodialysis (50% of drug in four 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 four-hour hemodialysis treatment (Table). (See table.)

Click on icon to see table/diagram/image

Pregabalin: In overdoses up to 15 g, no unexpected adverse effects were reported. In postmarketing experience, fatal outcomes in cases in which pregabalin has been taken in combination with other drugs have been reported with a pregabalin overdose as low as 800 mg per day. In none of these cases has pregabalin been established as the cause of death or in pregabalin monotherapy.
The most commonly reported adverse events observed when pregabalin was taken in overdose (dose range: 800 mg/day to 11,500 mg as a single dose) include affective disorder, somnolence, confusional state, depression, agitation, and restlessness.
There is no specific antidote for pregabalin. Treatment of pregabalin overdose should be symptomatic and supportive including monitoring of vital signs and observation of the clinical status of the patient. Consider administration of activated charcoal in the event of a potentially toxic ingestion. Activated charcoal is most effective when administered within one hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected.
Hemodialysis may be useful in patients with severe toxicity or those with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in four hours). Emesis is not recommended because of the potential for CNS depression and seizures.
Mecobalamin: Vitamin B₁₂ has a long history of safe use even at high dosages. The cobalt content and cyanide content (for cyanocobalamin) are not considered toxicologically relevant at usual doses. No harmful effects were reported in high levels of vitamin B₁₂ from food or supplement in healthy people. A tolerable upper intake level (UL) for vitamin B₁₂ has not been determined.

Hypersensitivity to pregabalin, mecobalamin (and to other forms of vitamin B₁₂), or to any component of the product.

Angioedema: There have been postmarketing reports of angioedema in patients, some without reported previous history/episode, during initial/acute and chronic treatment with pregabalin. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck, throat, and larynx/upper airway. There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Some of these patients did not have reported previous history/episode of angioedema. Discontinue pregabalin immediately in patients with these symptoms.
Exercise caution when prescribing pregabalin to patients who have had a previous episode of angioedema. Patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors or ACE-inhibitors) may be at increased risk of developing angioedema.
Hypersensitivity: There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with pregabalin. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin immediately in patients with these symptoms.
Serious Skin Reactions: There have been very rare postmarketing reports of serious cutaneous reactions, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), dermatitis exfoliative, bullous skin reactions, and erythema multiforme in patients treated with pregabalin. Most of the reports were in patients taking concomitant drugs also associated with the potential development of these serious skin reactions. Therefore, in most cases, causality in relation to pregabalin could not be clearly established. Patients should be advised that if they experience a skin rash, they should discontinue pregabalin treatment and contact their physician for assessment and advice.
Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including pregabalin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Anyone considering prescribing pregabalin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs 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.
Inform patients, their caregivers, and families that pregabalin and other AEDs increase the risk of suicidal thoughts and behavior and advise them 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. Report behaviors of concern immediately to healthcare providers.
Withdrawal Symptoms: After abrupt or rapid discontinuation of pregabalin, the following events have been reported: insomnia, headache, nausea, anxiety, diarrhea, flu syndrome, nervousness, depression, pain, convulsion, hyperhidrosis, and dizziness, suggestive of physical dependence. The patient should be informed about this at the start of the treatment.
Convulsions, including status epilepticus and grand mal convulsions, may occur during pregabalin use or shortly after discontinuing pregabalin.
Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of withdrawal of symptoms may be dose-related.
As with all AEDs, withdraw pregabalin gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If pregabalin is discontinued, taper the drug gradually over a minimum of one week.
Dizziness and Somnolence: Pregabalin causes dizziness and somnolence. Inform patients that pregabalin-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery.
There have also been reports of loss of consciousness, confusion, and mental impairment.
Substance Misuse, Abuse and Dependence: There have been postmarketing reports of substance misuse and abuse with pregabalin. As with any CNS drug, patients should be carefully evaluated for a history of substance abuse and observed for signs of pregabalin misuse or abuse (e.g., development of tolerance, increase in dose, drug-seeking behavior).
Monotherapy for Seizure Control: In patients where pregabalin was used as add-on therapy, there are insufficient data on seizure control when concomitant AEDs were withdrawn and pregabalin was used as monotherapy.
Encephalopathy: Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may precipitate encephalopathy. Some cases were reported in patients with a history of kidney or liver disease. Since there have been rare reports of renal failure with pregabalin, specific caution should be exercised when prescribing pregabalin to the elderly with age-related compromised renal function and patients with kidney disease or risk factors for renal failure.
Treatment of central neuropathic pain due to spinal cord injury: In general, CNS adverse reactions, particularly somnolence, was increased in the treatment of central neuropathic pain due to spinal cord injury. This may be attributed to an additive effect due to concomitant drugs (e.g., anti-spasticity agents) needed for this condition. This should be considered when prescribing pregabalin in this condition.
Peripheral Edema: In controlled studies, peripheral edema occurred more frequently in patients treated with pregabalin than in patients treated with placebo. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.
Congestive Heart Failure: There have been postmarketing 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. Pregabalin should be used with caution in these patients. Discontinuation of pregabalin may resolve the reaction.
Weight Gain: Pregabalin treatment may cause weight gain. Pregabalin-associated weight gain was related to dose and length of exposure, but did not appear to be associated with baseline body mass index, gender or age. Weight gain was not limited to patients with edema and was not necessarily due to edema-related events.
Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of pregabalin-associated weight gain are unknown.
While the effects of pregabalin-associated weight gain on glycemic control have not been systematically assessed in controlled and longer-term open label studies with diabetic patients, pregabalin treatment did not appear to be associated with loss of glycemic control.
In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycemic drugs.
Gastrointestinal Effect: There have been postmarketing reports of events related to reduce lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) in patients, some without reported previous history/episode, during initial/acute and chronic treatment with pregabalin, primarily in combination with other drugs that have the potential to produce constipation such as opioid analgesics. Some of these events were considered serious and required hospitalization. When pregabalin and opioids will be used in combination, measures to prevent constipation may be considered, particularly in female patients and the elderly as they may be at increased risk of experiencing lower gastrointestinal related events.
Renal Failure: There are reports of patients, with or without previous history, experiencing renal failure while receiving pregabalin alone or in combination with other drugs. Discontinuation of pregabalin should be considered as it has shown reversibility of this event in some cases. Caution is advised when prescribing pregabalin to the elderly or those with any degree of renal impairment.
Creatine Kinase Elevations: Treatment with pregabalin was associated with creatine kinase elevations. In premarketing studies, some patients had events reported as rhabdomyolysis; however the relationship between these myopathy events and pregabalin is not completely understood. Pregabalin should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.
Ophthalmological Effects: In controlled studies, a higher proportion of patients treated with pregabalin reported blurred vision than did patients treated with placebo. In the majority of cases, blurred vision resolved with continued dosing. If blurred vision persists, further assessment should be considered.
In postmarketing experience, visual adverse reactions have also been reported, including loss of vision, visual blurring or other changes of visual acuity, many of which were transient. Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.
Patients should be informed that if changes in vision occur, they should notify their physician. If visual disturbance persists, further assessment, including discontinuation of pregabalin, should be considered. More frequent assessments should be considered for patients who are already routinely monitored for ocular conditions.
Renal Impairment: There have been reports of patients, with or without previous history, experiencing renal failure while receiving pregabalin alone or in combination with other drugs. Discontinuation of pregabalin showed reversibility of this event in some cases. Because pregabalin is eliminated primarily by renal excretion, the dose of pregabalin should be adjusted as noted for elderly patients or those with renal impairment. In patients with a medical history of significant renal insufficiency, daily dosages should be reduced accordingly.
Effects on Ability to Drive and Use Machine: Pregabalin may have minor or moderate influence on the ability to drive and use machines. Pregabalin may cause dizziness and somnolence and therefore may have an influence on 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 medication affects their ability to perform these activities.
Use in Children: The safety and efficacy of pregabalin in pediatric patients have not been established.
Use in the Elderly: Pregabalin treatment has been associated with dizziness and somnolence, which may increase the occurrence of accidental injury (falls) in the elderly population.

Pregnancy: Pregabalin: Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Pregabalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Mecobalamin: Mecobalamin crosses the placenta. Supplementation with mecobalamin may improve the nutritional status of pregnancy women. However, data from clinical trials are inadequate. Pregnant women should only use higher doses if it is recommended by the physician.
Women of childbearing potential: Pregabalin: As the potential risk for humans is unknown, effective contraception must be used in women of childbearing potential.
Mecobalamin: No maternal or fetal complications have been associated with the use of vitamin B₁₂.
Labor and Delivery: The effects of pregabalin on labor and delivery in pregnant women are unknown.
Lactation: Pregabalin: Pregabalin is excreted in the milk of breastfeeding women. As the safety of pregabalin in infants is not known, breastfeeding is not recommended in women taking pregabalin. A decision should be made whether to discontinue breastfeeding or to discontinue pregabalin therapy, taking into consideration the benefit of breastfeeding for the child and the benefit of therapy for the mother. Patients should be advised to notify their physician if they are breastfeeding.
Mecobalamin: Mecobalamin appears in breast milk. It is compatible with lactation at usual dosages.

Pregabalin: Infections and infestations: Abscess, cellulitis, fungal infection, infection bacterial, infections, moniliasis, nasopharyngitis, gangrene peripheral, sepsis, sinusitis, viral infection.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Adenoma, carcinoma, cyst, neoplasm.
Blood and lymphatic system disorders: Anemia, chronic leukemia, coagulation disorder, cyanosis, ecchymosis, eosinophilia, erythrocytes abnormal, hypochromic anemia, iron deficiency anemia, leukemoid reaction, leukocytosis, leukopenia, lymphadenopathy, lymphangitis, lymphedema, lymphocytosis, lymphoma-like reaction, macrocytic anemia, megaloblastic anemia, myelofibrosis, neutropenia, pancytopenia, polycythemia, purpura, rupture of spleen, splenomegaly, thrombocythemia, thrombocytopenia, thrombocytopenic purpura.
Immune system disorders: Allergic reaction, anaphylactoid reaction, anaphylaxis, angioedema, hypersensitivity, immune system disorder, sarcoidosis.
Endocrine disorders: Adrenal insufficiency, diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, parathyroid disorder, prolactin increased, thyroid carcinoma, thyroid disorder, thyroiditis, thyroid neoplasia, thyroid neoplasm, virilism,
Metabolism and nutrition disorders: Acidosis, alcohol intolerance, anorexia, appetite increased, avitaminosis, calcium disorder, dehydration, enzymatic abnormality, fluid retention, glucose tolerance decreased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperlipemia, hyperkalemia, hypernatremia, hyperuricemia, hypocalcemia, hypochloremia, hypoglycemia, hypoglycemic reaction, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, hyperuricemia, impaired healing, ketosis, lactic acidosis, obesity, uremia.
Psychiatric disorders: Abnormal dreams, addiction, agitation, aggression, anorgasmia, anxiety, akathisia, apathy, aphasia, confusion, confusional state, decreased libido, delirium, delusions, depersonalization, depressed mood, depression, disinhibition, disorientation, drug dependence, elevated mood, euphoric mood, hallucination, hostility, increased libido, irritability, insomnia, manic reaction, mood swings, neurosis, panic attack, paranoid reaction, personality disorder, psychosis, psychotic depression, psychotic disorder, restlessness, schizophrenic reaction, suicide attempt, word finding difficult.
Nervous system disorders: Abnormal coordination, amnesia, arachnoiditis, ataxia, balance disorder, brain edema, burning sensation, cerebellar syndrome, cerebral infarct, cerebral ischemia, cerebrovascular disorder, circumoral paresthesia, CNS depression, CNS neoplasia, CNS stimulation, cognitive disorder, cogwheel rigidity, coma, convulsions (including grand mal and status epilepticus convulsions), dementia, disturbance in attention, dizziness, dizziness postural, dysarthria, dysautonomia, dysgraphia, dyskinesia, dystonia, encephalopathy, euphoria, extrapyramidal syndrome, facial paralysis, foot drop, Guillain-Barre syndrome, headache, hemiplegia, hypalgesia, hyperalgesia, hyperesthesia, hyperkinesia, hyperreflexia, hypesthesia, hypertonia, hypoesthesia, hypokinesia, hyporeflexia, hypotonia, incoordination, intention tremor, intracranial aneurysm, intracranial hypertension, lethargy, loss of consciousness, memory impairment, meningitis, mental impairment, migraine, movement disorder, multiple sclerosis, muscle spasticity, myoclonus, nervousness, neuralgia, neuritis, neuropathy, nystagmus, paralysis, paresthesia, parosmia, peripheral neuritis, psychomotor hyperactivity, sedation, sleep disorder, somnolence, speech disorder, stupor, subarachnoid hemorrhage, syncope, thinking abnormal, torticollis, tremor, trismus, twitching, withdrawal syndrome.
Eye disorders: Abnormality of accommodation, abnormal vision, altered visual depth perception, anisocoria, asthenopia, blepharitis, blindness, blurred vision, cataract not otherwise specified (NOS), cataract specified, color blindness, conjunctivitis, corneal lesion, corneal opacity, corneal ulcer, diplopia, dry eye, exophthalmos, extraocular palsy, eye disorder, eye hemorrhage, eye irritation, eye pain, eye swelling, glaucoma, increased lacrimation, iritis, keratitis, keratoconjunctivitis, lacrimation disorder, miosis, mydriasis, night blindness, ophthalmoplegia, optic atrophy, oscillopsia, papilledema, peripheral vision loss, photophobia, photopsia, ptosis, reduced visual acuity, refraction disorder, retinal artery occlusion, retinal degeneration, retinal depigmentation, retinal detachment, retinal disorder, retinal edema, retinal hemorrhage, scleritis, strabismus, uveitis, vision loss, visual brightness, visual disturbance, visual field defect, vitreous disorder.
Ear and labyrinth disorders: Deafness, ear disorder, ear pain, hyperacusis, otitis externa, otitis media, tinnitus, vertigo, vestibular disorder.
Cardiac disorders: Angina pectoris, aortic stenosis, arrhythmia, atrial arrhythmia, atrial flutter, atrial fibrillation, atrioventricular (AV) block (first-degree, second-degree, complete), bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cardiovascular disorder, congestive heart failure, coronary artery disorder, coronary occlusion, cor pulmonale, electrocardiogram abnormal, endocarditis, extrasystoles, heart arrest, heart block, heart failure, left heart failure, myocardial infarct, myocardial ischemia, nodal tachycardia, palpitations, pulmonary embolus, QT interval shortened, QT prolongation, sinus arrhythmia, sinus bradycardia, sinus tachycardia, ST segment depression, ST segment elevation, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, T wave inversion, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation, ventricular tachycardia.
Vascular disorders: Arterial anomaly, arteriosclerosis, carotid occlusion, carotid thrombosis, cerebral hemorrhage, cerebrovascular accident, deep thrombophlebitis, embolism lower extremity, flushing, hemorrhage, hot flushes, hypertension, hypotension, increased capillary fragility, occlusion, peripheral coldness, petechia, phlebitis, postural hypertension, postural hypotension, retinal vascular disorder, shock, thrombophlebitis, thrombosis, varicose vein, vascular anomaly, vascular disorder, vascular headache, vasculitis, vasodilatation.
Respiratory, thoracic, and mediastinal disorders: Apnea, aspiration pneumonia, asthma, atelectasis, bronchiectasis, bronchiolitis, carcinoma of lung, cough, cough increased, dyspnea, emphysema, epistaxis, flu syndrome, hemoptysis, hiccup, hyperventilation, hypoventilation, hypoxia, laryngeal neoplasia, laryngismus, laryngitis, lung disorder, lung edema, lung fibrosis, lung function decreased, nasal congestion, nasal dryness, nasal septum disorder, parosmia, pharyngitis, pharyngolaryngeal pain, pleural disorder, pleural effusion, pneumonia, pneumothorax, pulmonary edema, pulmonary hypertension, respiratory disorder, respiratory failure, rhinitis, snoring, sputum increased, throat tightness, voice alteration, yawn.
Gastrointestinal disorders: Abdomen enlargement, abdominal distention, abdominal pain, abnormal stools, aphthous stomatitis, ascites, bloody diarrhea, cardiospasm, cheilitis, colitis, constipation, diarrhea, dry mouth, duodenal ulcer, dysphagia, enteritis, enterocolitis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal impaction, fecal incontinence, flatulence, gastritis, gastroenteritis, gastroesophageal reflux disease, gastrointestinal carcinoma, gastrointestinal disorder, gastrointestinal disturbance, gastrointestinal hemorrhage, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, halitosis, hematemesis, hemorrhagic gastritis, intestinal obstruction, intestinal perforation, intestinal stenosis, intestinal ulcer, leukoplakia of the mouth, melena, mouth ulceration, nausea, necrotizing pancreatitis, oral hypoesthesia, oral moniliasis, pancreas disorder, pancreatitis, paralytic ileus, peptic ulcer, periodontal abscess, periodontitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, salivary gland enlargement, salivary hypersecretion, sialadenitis, stomach atony, stomach ulcer, stomach ulcer hemorrhage, stomatitis, swollen tongue, taste loss, taste perversion, tenesmus, tongue discoloration, tongue disorder, tongue edema, tooth caries, ulcerative colitis, ulcerative stomatitis, vomiting.
Hepatobiliary disorder: Biliary pain, bilirubinemia, cholecystitis, cholelithiasis, cholestatic jaundice, hepatitis, hepatoma, hepatomegaly, jaundice, liver fatty deposit, liver tenderness.
Skin and subcutaneous tissue disorders: Acne, alopecia, angioedema, blister, body odor, bullous skin reactions, cold sweat, cutaneous moniliasis, decreased sweating, decubitus ulcer, dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, face swelling, fungal dermatitis, furunculosis, granuloma, hair disorder, Henoch-Schonlein purpura, herpes simplex, herpes zoster, hirsutism, hyperhidrosis, ichthyosis, lichenoid dermatitis, maculopapular rash, melanosis, miliaria, nail disorder, papular rash, photosensitivity reaction, petechial rash, pruritus, psoriasis, purpuric rash, pustular rash, rash, seborrhea, skin atrophy, skin benign neoplasm, skin carcinoma, skin discoloration, skin disorder, skin hypertrophy, skin melanoma, skin necrosis, skin nodule, skin ulcer, Stevens-Johnson syndrome (SJS), subcutaneous nodule, sweating, Toxic Epidermal Necrolysis (TEN), urticaria, vesiculobullous rash.
Musculoskeletal and connective tissue disorders: Arthralgia, arthritis, arthrosis, back pain, bone disorder, bone neoplasm, bone pain, bursitis, cervical spasm, chondrodystrophy, generalized spasms, joint disorder, joint swelling, leg cramps, lupus erythematosus syndrome, muscle atrophy, muscle cramp, muscle spasms, muscle stiffness, muscle twitching, muscular weakness, musculoskeletal congenital anomaly, myalgia, myasthenia, myopathy, myositis, neck pain, neck rigidity, osteomyelitis, osteoporosis, pain in extremity, pain in limb, pathological fracture, pyogenic arthritis, rhabdomyolysis, rheumatoid arthritis, sarcoma, tendinous contracture, tendon disorder, tendon rupture, tenosynovitis.
Renal and urinary disorders: Acute kidney failure, albuminuria, bladder calculus, bladder carcinoma, bladder neoplasm, calcium crystalluria, cervix neoplasm, creatinine clearance decreased, cystitis, dysuria, glomerulitis, glycosuria, hematuria, hydronephrosis, kidney calculus, kidney function abnormal, kidney pain, nephritis, nephrosis, nocturia, oliguria, polycystic kidney, polyuria, pyelonephritis, pyuria, renal failure, suspicious papanicolaou smear, urate crystalluria, urethral pain, urethritis, urinary frequency, urinary incontinence, urinary retention, urinary tract infection, urinary urgency, urination impaired, urine abnormality, urogenital disorder, urolithiasis, uterine fibroids enlarged.
Reproductive system and breast disorders: Abnormal ejaculation, amenorrhea, balanitis, breast abscess, breast carcinoma, breast discharge, breast enlargement, breast neoplasm, breast pain, cervicitis, cervix disorder, delayed ejaculation, dysmenorrhea, dyspareunia, endometrial carcinoma, endometrial disorder, epididymitis, erectile dysfunction, female lactation, fibrocystic breast, gynecomastia, hypomenorrhea, impotence, leucorrhea, mastitis, menopause, menorrhagia, menstrual disorder, metrorrhagia, orchitis, ovarian cancer, ovarian disorder, pelvic pain, prostate neoplasia, prostatic cancer, prostatic disorder, salpingitis, sexual dysfunction, unintended pregnancy, urogenital anomaly, urogenital neoplasia, uterine disorder, uterine hemorrhage, vaginal hemorrhage, vaginal moniliasis, vaginitis, vulvovaginal disorder.
General disorders and administration site conditions: Asthenia, chest pain substernal, chest tightness, chills, death, edema, face edema, fall, fatigue, feeling abnormal, feeling drunk, gait abnormality, generalized edema, hangover effect, hernia, hypothermia, increased drug effect, malaise, mucous membrane disorder, pain, peripheral edema, peripheral swelling, pyrexia, reaction unevaluable, retroperitoneal fibrosis, sudden death, thirst, tolerance decreased, unexpected benefit.
Investigations: Abnormal laboratory test, decreased blood potassium, decreased drug level, decreased platelet count, decreased prothrombin, decreased weight, decreased white blood cell count, hormone level altered, increased alanine aminotransferase, increased alkaline phosphatase, increased aspartate aminotransferase, increased blood creatinine, increased blood creatinine phosphokinase, increased blood glucose, increased blood urea nitrogen, increased drug level, increased gamma globulins, increased gamma glutamyl transpeptidase, increased gonadotropic follicle stimulating hormone, increased nonprotein nitrogen, increased prostatic specific antigen, increased sedimentation rate, increased sodium, increased weight Injury, poisoning and procedural complications: Accidental injury, digitalis intoxication, injection site hemorrhage, injection site pain, injection site reaction, intentional injury, medication error, overdose (accidental, intentional).
Mecobalamin: Immune system disorders: Anaphylaxis, hypersensitivity reactions (to mecobalamin and other forms of Vitamin B₁₂), urticaria.
Metabolism and nutrition disorders: Anorexia.
Nervous system disorders: Dizziness, headaches, paresthesia, tremor.
Gastrointestinal disorders: Diarrhea, gastrointestinal disturbances, nausea, vomiting.
Skin and subcutaneous tissue disorders: Acneform eruptions, bullous eruption, pruritus, rash.
Renal and urinary disorders: Chromaturia.
General disorders and administration site conditions: Chills, fever, hot flushing, malaise.

Pregabalin: ACE inhibitors: Potential pharmacologic interaction with ACE inhibitors (e.g., increased risk of developing angioedema).
Gabapentin: The rate of pregabalin's absorption was reduced by approximately 26% (single dose administration) and 18% (multiple dose administration) based on lower C_max values; however, the extent of pregabalin absorption was unaffected by gabapentin coadministration.
Lorazepam, oxycodone and alcohol: Pregabalin may potentiate the effects of alcohol and lorazepam. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.
In postmarketing experience, there are reports of respiratory failure and coma in patients taking pregabalin alone or in combination with other CNS depressants.
Higher frequencies of weight gain and peripheral edema were reported in patients taking both pregabalin and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone.
As the thiazolidinedione class of antidiabetic drugs or pregabalin can cause weight gain and/or fluid retention alone or together, possibly exacerbating or leading to heart failure, caution should be exercised when co-administering pregabalin and these drugs.
Mecobalamin: Metformin: Metformin may decrease the absorption of vitamin B₁₂, which may be reversed with oral calcium supplementation.
Cholestyramine, colestipol: Cholestyramine and colestipol may decrease the enterohepatic reabsorption of B₁₂.
Chloramphenicol, colchicine, H₂-antagonists, neomycin, para-aminosalicylic acid, proton-pump inhibitors (e.g., omeprazole): These drugs may decrease the absorption of vitamin B₁₂ from the gastrointestinal tract.
Nitrous oxide: Nitrous oxide forms a complex with cobalt in mecobalamin. Since mecobalamin is a cofactor of methionine synthase, inhalation of nitrous oxide may inactivate this enzyme.
Folate and vitamin B₆: Folic acid and vitamin B₆ may work synergistically with vitamin B₁₂ in lowering homocysteine levels.
Oral contraceptives: Oral contraceptives may reduce the serum concentration of vitamin B₁₂.
Most antibiotics, methotrexate, pyrimethamine: These drugs may invalidate folic acid and vitamin B₁₂ diagnostic blood assays.

Store at temperatures not exceeding 30°C. Store in a cool, dry place. Protect from light.

Anticonvulsants / Drugs for Neuropathic Pain

N02BF02 - pregabalin ; Belongs to the class of gabapentinoids. Used to relieve pain and other conditions.

Rx