Upnuron Tablets

Pregabalin (Prolonged release), Methylcobalamin and Nortriptyline Hydrochloride Tablets

Each film coated bilayered tablet contains :

Pregabalin IP (Prolonged Release) 75 mg

Methylcobalamin IP 1500 mcg

Nortriptyline Hydrochloride IP

equivalent to Nortriptyline 10 mg

Excipients q.s.

Colour : Sunset Yellow Lake (In Methylcobalamin & Nortriptyline layer)

Bilayered Film Coated Tablets

4.1 Therapeutic indication

For the treatment of patient with diabetic peripheral neuropathic pain with coexistent Vitamin B12 Deficiency.

4.2 Posology and method of administration

One tablet daily or as directed by the Physician  Route of Administration : To be taken orally

4.3 Contraindications

Known hypersensitivity to any of the active constituents.

4.4 Special warnings and precautions for use Nortriptyline

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour (suicidality) or unusual changes in behaviour, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behaviour (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

Pregabalin

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

Hypersensitivity reactions

There have been reports in the post-marketing experience of hypersensitivity reactions, including cases of angioedema. 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. There have also been postmarketing reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medicinal product.

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. In the clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction and visual field changes was greater in pregabalin-treated patients than in placebo-treated patients; the incidence of fundoscopic changes was greater in placebo-treated patients. In the post-marketing 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.

4.5 Interaction with other medicinal products and other forms of interaction

Mecobalamin

No known drug interaction

Pregabalin

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.

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 ethinyloestradiol

Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyloestradiol does not influence the steady-state pharmacokinetics of either substance.

Central nervous system 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 postmarketing experience, there are reports of respiratory failure and coma in patients taking pregabalin and other central nervous system (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 pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults

Nortriptyline HCL

Administration of reserpine during therapy with a tricyclic antidepressant has been shown to produce a “stimulating” effect in some depressed patients. Close supervision and careful adjustment of the dosage are required when nortriptyline HCl is used with other anticholinergic drugs and sympathomimetic drugs. Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressant. The patient should be informed that the response to alcohol may be exaggerated. A case of significant hypoglycemia has been reported in a type II diabetic patient maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline (125 mg/day).

4.6 Fertility, pregnancy and lactation

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.

Women of child bearing potential / Contraception in males and females As the potential risk for humans is unknown, effective contraception must be used in women of child bearing potential.

Pregabalin should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus).

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. A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats have shown adverse reproductive and developmental effects. The clinical relevance of these findings is unknown.

4.7 Effects on ability to drive and use machines

Nortriptyline has moderate influence on the ability to drive and use machines. Nortriptyline may impair the mental and/or physical abilities required for the performance of hazardous tasks, such as operating machinery or driving a car; therefore, the patient should be warned accordingly.

4.8 Undesirable effects

Mecobalamin

Adverse reactions were reported in 13 of 2,872 patients (0.45 %). (At the end of the re-examination period).

Clinically significant adverse reactions (incidence unknown).

Anaphylactoid reaction

Anaphylactoid reaction such as decrease in blood pressure or dyspnea, may occur. Patients should be carefully observed. In the event of such symptoms, treatment should be discontinued immediately and appropriate measures taken.

Pregabalin

The pregabalin clinical programme involved over 8900 patients exposed to pregabalin, of whom over 5600 were in double-blind placebo-controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 12% for patients receiving pregabalin and 5% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com Website : http://www.zuventus.co.in/safety.aspx By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

No data are available about overdosage for Pregabalin (PR) 75 mg + Mecobalamin 1500 mcg +Nortriptyline10mg FilmCoatedBilayered tablet in humans.

5.1 Mechanism of action / Pharmacodynamic properties

Mecobalamin

• Mecobalamin is a Neurotropic and acts as a growth promoter for nerve cells, a property which helps to regenerate Central and Peripheral nervous tissue damaged in disorder such as diabetic peripheral neuropathy.
• Mecobalamin acts as a methyl donor for the synthesis of Lecithin, a major component of the Myelin sheath.
• Mecobalamin facilitates methylation of t-RNA which play a fundamental role in protein

synthesis and stimulates methionine synthesis and helps to restore normal levels of RNA in nerve cells.

• Mecobalamin acts as a co-factor in the enzyme methionine synthase which regenerates methionine thus generating an increased supply of S-Adenosyl Methionine (SAMe) and SAMe protects from Neurotoxicity.
• Mecobalamin normalizes Nerve cell conduction by healing the damaged nerve cells and restores delayed synaptic transmission and diminished neurotransmitters to normal.
• Mecobalamin improves the excitability of the nerve fibres and thus improves the neurotransmission.

Pregabalin

The active substance, pregabalin, is a gamma-aminobutyric acid analogue [(S)-3- (aminomethyl)-5-methylhexanoic acid]. Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system.

Nortriptyline HCl

The mechanism of mood elevation by tricyclic antidepressants is at present unknown. Nortriptyline HCl is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine. Studies suggest that nortriptyline HCl interferes with the transport, release, and storage of catecholamines. Operant conditioning techniques in rats and pigeons suggest that nortriptyline HCL has a combination of stimulant and depressant properties.

5.2 Pharmacokinetic properties

Pregabalin

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

Nortriptyline HCl

Nortriptyline is widely distributed throughout the body and is extensively bound to plasma and tissue protein. Plasma concentrations of Nortriptyline may vary widely between individuals and no simple correlation with therapeutic response has been established.

Mecobalamin

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. Gastrointestinal absorption of vitamin B12 depends on the presence of sufficient intrinsic factor and calcium ions. Intrinsic factor deficiency causes pernicious anaemia, which may be associated with subacute combined degeneration of the spinal cord. 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.

No known animal toxicology data

Pregabalin is a medication used to treat epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorder. Its use for epilepsy is as an add-on therapy for partial seizures with or without secondary generalization in adults. Some off-label uses of pregabalin include restless leg syndrome, prevention of migraines, anxiety disorders, and alcohol withdrawal. When used before surgery it does not appear to affect pain after surgery but may decrease the use of opioids.

Mecobalamin, is a cobalamin, a form of vitamin B12. It differs from cyanocobalamin in that the cyano at the cobalt is replaced with a methyl group. Mecobalamin features an octahedral cobalt(III) centre and can be obtained as bright red crystals. From the perspective of coordination chemistry, Mecobalamin is notable as a rare example of a compound that contains metal-alkyl bonds. Nickel-methyl intermediates have been proposed for the final step of methanogenesis. Mecobalamin is equivalent physiologically to vitamin B12, and can be used to prevent or treat pathology arising from a lack of vitamin B12 intake (vitamin B12 deficiency). Mecobalamin is also used in the treatment of peripheral neuropathy, diabetic neuropathy, and as a preliminary treatment for amyotrophic lateral sclerosis. Mecobalamin that is ingested is not used directly as a cofactor, but is first converted by MMACHC into cob(II)alamin. Cob(II)alamin is then later converted into the other 2 forms, adenosylcobalamin and Mecobalamin for use as cofactors. That is, Mecobalamin is first dealkylated and then regenerated.

Nortriptyline, is a tricyclic antidepressant (TCA) used to treat clinical depression. Another licensed use for it is in the treatment of childhood bedwetting. Off-label uses include chronic pain and migraine and labile affect in some neurological disorders. Chemically, it is a

secondary amine dibenzocycloheptene and pharmacologically it is classed as a secondgeneration TCA. Nortriptyline has less anticholinergic (like dry mouth, constipation, blurred vision, etc.), antihistamine (like sedation and possibly weight gain), antiadrenergic (like orthostatic hypotension), and cardiotoxic (heart-toxic, namely the capacity of these drugs to interfere with normal heart rhythm) effects than the older first-generation TCAs. Nortriptyline is the major active metabolite of amitriptyline, a first-generation TCA. It is the N-desmethyl metabolite of amitriptyline. Like amitriptyline it works by inhibiting the reuptake of serotonin and norepinephrine, thereby enhancing synaptic signalling via these neurotransmitters. It preferentially inhibits the reuptake of norepinephrine over serotonin, which is the opposite to amitriptyline.

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack

8.3 Packaging information

Alu-Alu blister strip of 10 tablets.

8.4 Storage and handing instructions

Store at a temperature not exceeding 30°C, protected from light & moisture.

Keep out of reach of children.

Do not take this medicine

if you are allergic to the active substance or any of the other ingredients of this medicine

Warnings and precautions

• Talk to your doctor or pharmacist before taking this medicine:
• Some patients taking Upnuron have reported symptoms suggesting an allergic reaction. These symptoms include swelling of the face, lips, tongue, and throat, as well as diffuse skin rash. Should you experience any of these reactions, you should contact your physician immediately.
• Upnuron has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in elderly patients. Therefore, you should be careful until you are used to any effect the medicine might have.
• Upnuron may cause blurring or loss of vision, or other changes in eyesight, many of which are temporary. You should immediately tell your doctor if you experience any changes in your vision.
• Some patients with diabetes who gain weight while taking Upnuron may need an alteration in their diabetic medicines.
• Certain side effects may be more common, such as sleepiness, because patients with spinal cord injury may be taking other medicines to treat, for example, pain or spasticity, that have similar side effects to Upnuron and the severity of these effects may be increased when taken together.
• There have been reports of heart failure in some patients when taking Upnuron; these patients were mostly elderly with cardiovascular conditions.

Before taking this medicine you should tell your doctor if you have a history of heart disease.

• There have been reports of kidney failure in some patients when taking Upnuron. If while taking Upnuron you notice decreased urination, you should tell your doctor as stopping the medicine may improve this.
• A small number of people being treated with anti-epileptics such as Upnuron have had thoughts of harming or killing themselves. If at any time you have these thoughts, immediately contact your doctor.
• When Upnuron is taken with other medicines that may cause constipation (such as some types of pain medicines) it is possible that gastrointestinal problems may occur (e.g. constipation, blocked or paralysed bowel). Tell your doctor if you experience constipation, especially if you are prone to this problem.
• Before taking this medicine you should tell your doctor if you have a history of alcoholism or any drug abuse or dependence. Do not take more medicine than prescribed.
• There have been reports of convulsions when taking Upnuron or shortly after stopping Upnuron. If you experience a convulsion, contact your doctor immediately.
• There have been reports of reduction in brain function (encephalopathy) in some patients taking Upnuron when they have other conditions. Tell your doctor if you have a history of any serious medical conditions, including liver or kidney disease.
• There have been reports of breathing difficulties. If you have nervous system disorders, respiratory disorders, renal impairment, or you are older than 65, your doctor may prescribe you a different dosing regimen. Contact your doctor if you experience trouble breathing or shallow breaths.
• Serious skin rashes including Stevens-Johnson syndrome, toxic epidermal necrolysis have been reported in association with Upnuron. Stop using Upnuron and seek medical attention immediately if you notice any of the symptoms related to these serious skin reactions.

14 October 2022