Nervite

Uses

Nortriptyline is used for the treatment of depression and nocturnal enuresis.

Pregabalin is used for the management of neuropathic pain associated with diabetic peripheral neuropathy and management of post-herpetic neuralgia. It is also used for the adjunctive therapy for adult patients with partial onset seizures. It can be used for the management of fibromyalgia and neuropathic pain associated with spinal cord injury.

Nervite is also used to associated treatment for these conditions: Irritable Bowel Syndrome (IBS), Major Depressive Disorder (MDD), Myofascial Pain Syndrome, Orofacial Pain, Pain, Chronic, Post-Herpetic Neuralgia (PHN)Diabetic Peripheral Neuropathic Pain (DPN), Epilepsies, Fibromyalgia, Generalized Anxiety Disorder (GAD), Neuropathic Pain, Partial-Onset Seizures, Peripheral Neuropathic Pain, Peripheral neuropathy, Postherpetic Neuralgia

How Nervite works

Though prescribing information does not identify a specific mechanism of action for nortriptyline, is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at the level of the beta-adrenergic receptors. It displays a more selective reuptake inhibition for noradrenaline, which may explain increased symptom improvement after nortriptyline therapy. Tricyclic antidepressants do not inhibit monoamine oxidase nor do they affect dopamine reuptake. As with other tricyclics, nortriptyline displays affinity for other receptors including mACh receptors, histamine receptors, 5-HT receptors, in addition to other receptors.

Although the mechanism of action has not been fully elucidated, studies involving structurally related drugs suggest that presynaptic binding of pregabalin to voltage-gated calcium channels is key to the antiseizure and antinociceptive effects observed in animal models.

By binding presynaptically to the alpha2-delta subunit of voltage-gated calcium channels in the central nervous system, pregabalin modulates the release of several excitatory neurotransmitters including glutamate, substance-P, norepinephrine, and calcitonin gene related peptide. In addition, pregabalin prevents the alpha2-delta subunit from being trafficked from the dorsal root ganglia to the spinal dorsal horn, which may also contribute to the mechanism of action.

Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA or benzodiazepine receptors.

Dosage

Nervite dosage

Depression:

• Adult: Low dose initially increased as necessary to 75-100 mg daily in divided doses or as a single dose (max. 150 mg daily)
• Adolescent & Elderly: 30-50 mg daily in divided doses; Child not recommended for depression

Nocturnal enuresis:

• Child 7 years: 10 mg
• 8-11 years: 10-20 mg
• Over 11 years: 25-35 mg, 30 minutes before bedtime; max period of treatment (including gradual withdrawal) 3 months- full physical examination and ECG before further course.

Neuropathic pain associated with diabetic peripheral neuropathy: The maximum recommended dose of Pregabalin is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Dosing should begin at 50 mg three times a day (150 mg/day) and may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

Post-herpetic neuralgia: The recommended dose of Pregabalin is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Dosing should begin at 75 mg two times a day, or 50 mg three times a day (150 mg/day) and may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

Adjunctive therapy for adult patients with partial onset seizures: Pregabalin at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. The total daily doseshould be divided and given either two or three times daily. In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day.

Management of Fibromyalgia: The recommended dose of Pregabalin for fibromyalgia is 300 to 450 mg/day. Dosing should begin at 75 mg two times a day (150 mg/day) and may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day).

Neuropathic pain associated with spinal cord injury: The recommended dose range is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability.

.Patients who do not experience sufficient pain relief after treatment with 300 mg/day and who tolerate pregabalin may be treated with up to 300 mg two times a day. Neurolin® capsules can be taken without regards to meals.

Side Effects

The most common side effects include dry mouth, sedation, constipation and increased appetite, mild blurred vision, tinnitus, often euphoria and mania. An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects and should be avoided.

The most common side effects include dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and abnormal thinking.

Toxicity

The oral LD50 of nortriptyline in the rat is 405 mg/kg.Symptoms of overdose with nortriptyline include cardiac arrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, convulsions, coma, and CNS depression. Changes in the electrocardiogram, particularly in QRS segment, may be indicative of tricyclic antidepressant toxicity.

In a systematic review that included 38 randomized controlled trials, there were 20 identified adverse effects that were significantly associated with pregabalin, most of which involve the central nervous system and cognition. The identified adverse effects include vertigo, dizziness, balance disorder, incoordination, ataxia, blurred vision, diplopia, amblyopia, somnolence, confusional state, tremor, disturbance in attention, abnormal thinking, asthenia, fatigue, euphoria, edema, peripheral edema, dry mouth, and constipation .

The most common symptoms of pregabalin toxicity (dose range includes 800 mg/day and single doses up to 11,500 mg) include somnolence, confusion, restlessness, agitation, depression, affective disorder and seizures.

Since there is no antidote for pregabalin overdose, patients should receive general supportive care. If appropriate, gastric lavage or emesis may help eliminate unabsorbed pregabalin (healthcare providers should take standard precautions to maintain the airway).

Pregabalin pharmacokinetic properties suggest that extra-corporeal elimination methods including haemodialysis, may be useful in situations of severe toxicity. However, there are cases where patients have presented with very high serum levels of pregabalin and have been successfully managed with supportive care alone.

Precaution

Not intended for treatment of bipolar depression. Avoid abrupt withdrawal. Patient at risk of seizures, with DM, narrow angle glaucoma, urinary retention, prostatic hyperplasia, chronic constipation, history of CV disease. Renal and hepatic impairment. Elderly, childn. Pregnancy and lactation.

Discontinuation of Pregabalin without tapering may produce insomnia, nausea, headache and diarrhea. So it should be tapered gradually over a minimum of 1 week rather than discontinued abruptly. Creatinine kinase may be elevated if treated with Pregabalin. It should be discontinued rapidly if myopathy is diagnosed or suspected or if creatinine kinase is elevated markedly.

Interaction

Nortriptyline should not be given with adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, phenylpropanolamine, drugs that are metabolized by CYP4502D6, MAOIs, guanethidine, debrisoquine, bethanidine, clonidine and reserpine etc. Barbiturates may increase the rate of metabolism of nortriptyline.

Volume of Distribution

The apparent volume of distribution (Vd)β, estimated after intravenous administration is 1633 ± 268 L within the range of 1460 to 2030 (21 ± 4 L/kg). Nortriptyline crosses the placenta and is found in the breast milk. It distributes to the heart, lungs, brain, and the liver.

After oral administration of pregabalin, the reported apparent volume of distribution is roughly 0.5 L/kg.

Although pregabalin is not very lipophilic, it is able to cross the blood brain barrier(BBB). System L transporters facilitate the transport of large amino acids across the BBB and it has been confirmed that pregabalin is a substrate. This information suggests that system L transporters are responsible for pregabalin uptake into the BBB.

In rat models, pregabalin has been shown to cross the placenta.

Elimination Route

Nortriptyline is readily absorbed in the gastrointestinal tract with extensive variation in plasma levels, depending on the patient. This drug undergoes first-pass metabolism and its plasma concentrations are attained within 7 to 8.5 hours after oral administration. The bioavailability of nortriptyline varies considerably and ranges from 45 to 85%.

After oral dosing administered in the fasted state, pregabalin absorption is rapid, and extensive. Pregabalin oral bioavailability is reported to be ≥90% regardless of the dose. Cmax is attained within 1.5 hours after single or multiple doses, and steady state is attained within 24-48 hours with repeated administration. Both Cmax and AUC appear to be dose proportional.

Food decreases the rate of pregabalin absorption and as a result, lowers the Cmax by an estimated 25-30% and increases the Tmax to approximately 3 hours. However, the effect of food does not appear to impact the total absorption of pregabalin in a way that is clinically relevant. As a result, pregabalin can be administered with or without food.

Half Life

The average plasma half-life of nortriptyline in healthy volunteers is about 26 hours, but is said to range from 16 to 38 hours. One study mentions a mean half-life of about 39 hours.

The elimination half life of pregabalin is 6.3 hours.

Clearance

The average plasma clearance of nortriptyline in a study of healthy volunteers was 54 L/h. The average systemic clearance of nortriptyline is 30.6 ± 6.9 L / h, within the range of 18.6 to 39.6 L/hour.

In young healthy subjects the mean renal clearance is estimated to be 67.0 to 80.9 mL mL/min. Given pregabalin's lack of plasma protein binding, this clearance rate suggests that renal tubular reabsorption is involved.

Elimination Route

Nortriptyline and its metabolites are mainly excreted in the urine, where only small amounts (2%) of the total drug is recovered as unchanged parent compound. Approximately one-third of a single orally administered dose is excreted in urine within 24 hours. Small amounts are excreted in feces via biliary elimination.

Pregabalin is almost exclusively eliminated in the urine.

Further, based on preclinical studies, pregabalin does not appear to undergo racemization to the R enantiomer in the body.

Pregnancy & Breastfeeding use

The safety of nortriptyline for use in pregnancy has not been established. Nortriptyline should only be given during pregnancy when there are no alternatives and benefit outweighs risk.

Pregnancy category C. So it should only used if potential benefit justifies the potential risks to the fetus.

Nursing mother: It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. So it should be used in nursing mother only if there is a clear benefit over the risk.

Contraindication

Nortriptyline is contraindicated in patients with hypersensitivity to nortriptyline. Concomitant administration with MAOI is contraindicated. Do not use with or within 2 weeks of stopping an MAOI. Nortriptyline is contraindicated during the acute recovery period after myocardial infarction.

Pregabalin is contraindicated in patients with known hypersensitivity to Pregabalin or any of its components.

Special Warning

Use in children & adolescents: The safety and effectiveness of Pregabalin have not been established in patients below the age of 18 years.

Use in elderly (Over 65 years of age): No dosage adjustment is necessary in elderly patients. Overdose: In overdoses up to 15 g, no unexpected adverse effects were reported.

Paediatric use: The safety and efficacy of pregabalin in paediatric patients have not been established.

Acute Overdose

Symptoms: Severe hypotension, cardiac dysrhythmias, shock, CHF, pulmonary oedema, convulsions, and CNS depression, including coma; changes in ECG.

Management: Symptomatic and supportive treatment. Admin IV Na bicarbonate, benzodiazepines. Admin activated charcoal to reduce absorption. Emesis is contraindicated. Initiate cardiac monitoring and observe for signs of CNS or resp depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures.

Storage Condition

Store at 15-30° C. Protect from light and moisture.

Store at a cool & dry place, protected from light and moisture. Keep out of reach of the children.

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