Composition
PREGABID NT 50
Each film coated tablet contains:
Pregabalin 50 mg + Nortriptyline 10 mg
Colour : Ferric Oxide Yellow & Titanium
Dioxide
PREGABID NT 75
Each film coated tablet contains:
Pregabalin 75 mg + Nortriptyline 10 mg
Colour : Ferric Oxide Yellow & Titanium
Dioxide

Indication & Usage

    PREGABID NT is indicated for:
  • Treatment of pain associated with various neuropathic conditions in adults such as: Diabetic peripheral neuropathy, Post herpetic neuralgia, Neuropathic low back pain, Spinal cord injury-associated pain, Central post-stroke pain, Trigeminal neuralgia

Dosage & administrations

  • Start with one PREGABID NT 50 tablet orally thrice daily (t.i.d.) or PREGABID NT 75 twice daily for the first 3-7 days (daily dose: Pregabalin 150 mg + Nortriptyline 30 mg).
  • Thereafter, depending on patient’s response and tolerability, dose can be increased to daily dose: Pregabalin 300 mg + Nortriptyline 60 mg.

Warning and Precautions

  • Withdrawal: Discontinuation of PREGABID NT should be done over a minimum of 1 week.
  • Tumorigenic potential: In lifetime carcinogenicity study in mice, pregabalin was associated with a high incidence of hemangiosarcoma. The clinical significance of this is unknown.
  • PREGABID NT may cause dizziness, somnolence, blurred vision, and other central nervous system (CNS) signs and symptoms.
  • Pregabalin may cause edema and weight gain. Angioedema (e.g., swelling of the throat, head and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment.
  • Patients who require concomitant treatment with CNS depressants such as opioids or benzodiazepines should be informed that they may experience additive CNS side effects, such as somnolence.
  • Consuming alcohol while taking PREGABID NT should be avoided.

Use in special population

  • Pregnancy & Lactation: Pregnancy Category C. Breast-feeding is avoidable if taking PREGABID NT.

Drug-Drug interactions

  • Pregabalin may potentiate the effects of ethanol and lorazepam.
  • Nortriptyline: Close supervision and careful adjustment of the dosage are required when nortriptyline hydrochloride 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.
  • Administration of reserpine during therapy with a tricyclic antidepressant has been shown to produce a “stimulating” effect in some depressed patients.
  • Drugs Metabolized by cytochrome P450 2D6 (CYP2D6) – Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by CYP2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA). The drugs that inhibit CYP2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for CYP2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide).
  • Caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of TCAs with drugs that can inhibit cytochrome CYP2D6 may require lower doses than usually prescribed for either the TCA or the other drug.

Adverse reactions

  • The most commonly adverse events for Pregabalin included dizziness, somnolence, peripheral edema, headache, blurred vision and constipation.
  • The majority (85%) of these (and other) adverse events were of mild-to-moderate intensity.
  • The most commonly reported side effects with nortriptyline are hypotension, sedation, dry mouth, seizures, weight gain, gynecomastia in the male, and breast enlargement and galactorrhea in the female.

Overdose

  • There is no specific antidote for overdose with Pregabalin.
  • If indicated, elimination of unabsorbed drug may be attempted by gastric lavage; usual precautions should be observed to maintain the airway.
  • General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.
  • Hemodialysis results in significant clearance of Pregabalin (approximately 50% in 4 hours) and may be required in some cases.
  • Treatment for nortriptyline overdose: Symptomatic and supportive therapy is recommended.
  • Activated charcoal may be more effective than lavage to reduce absorption.

Contraindication

  • Hypersensitivity to Pregabalin or Nortriptyline
  • Angioedema and hypersensitivity reactions have occurred in patients receiving Pregabalin therapy
  • Recent myocardial infarction, any degree of heart block or other cardiac arrhythmias
  • Severe liver disease.
  • Nortriptyline is contra-indicated for the nursing mother and for children under the age of six years.

Composition
Lamez 25
Each uncoated dispersible tablet contains:
Lamotrigine IP 25 mg
Excipients ……..Q.S
Lamez 50
Each uncoated dispersible tablet contains:
Lamotrigine IP 50 mg
Excipients ……..Q.S
Lamez 100
Each uncoated dispersible tablet contains:
Lamotrigine IP 100 mg
Excipients ……..Q.S
Lamez OD 25
Each uncoated sustained release tablet contains:
Lamotrigine IP 25 mg
Excipients ……..Q.S
Lamez OD 50
Each uncoated sustained release tablet contains:
Lamotrigine IP 50 mg
Excipients ……..Q.S
Lamez OD 100
Each uncoated sustained release tablet contains:
Lamotrigine IP 100 mg
Excipients ……..Q.S
Lamez OD 150
Each uncoated sustained release tablet contains:
Lamotrigine IP 150 mg
Excipients ……..Q.S
Lamez OD 200
Each uncoated sustained release tablet contains:
Lamotrigine IP 200 mg
Excipients ……..Q.S

Indication & Usage

Lamotrigine is indicated for:

Epilepsy—adjunctive therapy in patients aged 2 years and older:

  • Partial-onset seizures
  • Primary generalized tonic-clonic seizures
  • Generalized seizures of Lennox-Gastaut syndrome

Epilepsy—monotherapy in patients aged 16 years and older: Conversion to monotherapy in patients with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug.

Bipolar disorder: Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy.

Limitations of Use: Treatment of acute manic or mixed episodes is not recommended. Effectiveness of LAMOTRIGINE in the acute treatment of mood episodes has not been established.

Clinical Pharmacology

Pharmacodynamics

  • The results of pharmacological studies suggest that lamotrigine is a use- and voltage-dependent blocker of voltage gated sodium channels. It inhibits sustained repetitive firing of neurones and inhibits release of glutamate (the neurotransmitter which plays a key role in the generation of epileptic seizures). These effects are likely to contribute to the anticonvulsant properties of lamotrigine .
  • In contrast, the mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been established, although interaction with voltage gated sodium channels is likely to be important.

Pharmacokinetics

Absorption

  • Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine tablets for oral suspension were found to be equivalent, whether administered as dispersed in water, chewed and swallowed, or swallowed whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption. In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets, whether disintegrated in the mouth or swallowed whole with water, were equivalent to the lamotrigine compressed tablets swallowed with water.

Dose Proportionality

  • In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice daily.

Distribution

  • Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.

Protein Binding

  • Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.

Metabolism

  • Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

Enzyme Induction

  • The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.
  • Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in CL/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation

Dosage & Administration

Orally disintegrating tablets should be placed onto the tongue and moved around in the mouth. The tablet will disintegrate rapidly, can be swallowed with or without water, and can be taken with or without food

Epilepsy (patients aged >12 yrs)

  • For Patients TAKING Valproate: Wks 1&2: 25 mg every other day,Wks 3&4: 25 mg every day,Wk 5: 50 mg every day,Wk 6: 100 mg every day,Wk 7: 150 mg every day
  • Maintenance range (Wk 8 onwards): 200-250 mg every day
  • For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate.Wks 1&2: 25 mg daily,Wks 3&4: 50 mg daily,Wk 5: 100 mg daily #,Wk 6: 150 mg daily #,Wk 7: 200 mg daily #
  • Maintenance range (Wk 8 onwards): 300-400 mg daily#[# Given in two divided doses]
  • For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone and NOT TAKING Valproate .Wks 1&2: 50 mg every day,Wks 3&4: 100 mg every day#,Wk 5: 200 mg every day#,Wk 6: 300 mg every day#,Wk 7: 400 mg every day#
  • Maintenance range (Wk 8 onwards): 400-600 mg daily# [# Given in two divided doses]

Conversion from Adjunctive Therapy with Valproate to Monotherapy with LAMEZ in Patients ≥16 Years of Age

  • Step 1: LAMEZ - Achieve a dose of 200 mg/day according to guidelines above (if not already on 200 mg/day); Valproate - Maintain previous stable dose
  • Step 2: LAMEZ - Maintain at 200 mg/day; Valproate - Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and then maintain the dose of 500 mg/day for 1 week
  • Step 3: LAMEZ - Increase to 300 mg/day and maintain for 1 week; Valproate – Simultaneous-ly decrease to 250 mg/day and maintain for 1 week
  • Step 4: LAMEZ - Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day; Valproate - Discontinue

Escalation Regimen for LAMEZ Tablets for Patients with Bipolar Disorder

  • For Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin and Not Taking Valproate -Wks 1&2: 25 mg daily, Wks 3&4: 50 mg daily,Wk 5: 100 mg daily#,Wk 6: 200 mg daily#,Wk 7: 200 mg daily#[# Given in two divided doses],
  • For Patients TAKING Valproate:Wks 1&2: 25 mg every other day,Wks 3&4: 25 mg daily,Wk 5: 50 mg daily,Wk 6: 100 mg daily#,Wk 7: 100 mg daily#[# Given in two divided doses]
  • For Patients Taking Carbamazepine, Phenytoin,,Phenobarbital, Primidone, or Rifampin† and Not Taking Valproate Wks 1&2: 50 mg daily Wks 3&4: 100 mg daily# Wk 5: 200 mg daily# Wk 6: 300 mg daily# Wk 7: Up to 400 mg daily# [# Given in two divided doses]

Contraindications

  • Hypersensitivity to the drug or its ingredients.

Warnings And Precautions

  • Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly not drug related.
  • Hemophagocytic lymphohistiocytosis: Consider this diagnosis and evaluate patients immediately if they develop signs or symptoms of systemic inflammation. Discontinue LAMOTRIGINE if an alternative etiology is not established.
  • Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms, may be fatal or life threatening. Early signs may include rash, fever, and lymphadenopathy. These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure. LAMOTRIGINE should be discontinued if alternate etiology for this reaction is not found.
  • Cardiac rhythm and conduction abnormalities: Avoid LAMOTRIGINE in patients with certain underlying cardiac disorders or arrhythmias.
  • Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome. Monitor for signs of anemia, unexpected infection, or bleeding.
  • Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors.
  • Aseptic meningitis: Monitor for signs of meningitis.
  • Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct.

Adverse Reactions

  • Epilepsy: Most common adverse reactions (incidence ≥10%) in adults were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥10%) reported in children included vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, and tremor.
  • Bipolar disorder: Most common adverse reactions (incidence >5%) in adults were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia.

Drug Interactions

  • Valproate increases lamotrigine concentrations more than 2-fold.
  • Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin decrease lamotrigine concentrations by approximately 40%.
  • Estrogen-containing oral contraceptives decrease lamotrigine concentrations by approximately 50%.
  • Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease lamotrigine exposure by approximately 50% and 32%, respectively.
  • Coadministration with organic cationic transporter 2 substrates with narrow therapeutic index is not recommended

Use In Specific Populations

  • Pregnancy: Based on animal data may cause fetal harm
  • Hepatic impairment: Dosage adjustments required in patients with moderate and severe liver impairment
  • Renal impairment: Reduced maintenance doses may be effective for patients with significant renal impairment

Overdose

Human Overdose Experience

  • Overdoses involving quantities up to 15 g have been reported for LAMOTRIGINE, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay.

Management of Overdose

  • There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced; usual precautions should be taken to protect the airway. It should be kept in mind that immediate-release lamotrigine is rapidly absorbed [see Clinical Pharmacology (12.3)]. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of LAMOTRIGINE

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INTAS PHARMACEUTICALS LTD.
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Email: alecta@intaspharma.com