Larik 75

Pregabalin.

Each hard gelatin capsule contains Pregabalin 75 mg.

Pharmacotherapeutic group: Antiepileptics, other antiepileptics. ATC code: N03AX16.
Pharmacology: Pharmacodynamics: The active substance, pregabalin, is a gamma-aminobutyric acid analogue ((S)-3-(aminomethyl)-5-methylhexanoic acid).
Mechanism of Actions: Pregabalin binds to an auxiliary subunit (alpha-2-delta protein) of voltage-gated calcium channels in the CNS.
Evidence from animal models with nerve damage has shown that pregabalin reduces calcium dependent release of pronociceptive neurotransmitter in the spinal cord possibly by disrupting calcium trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage suggest the antinociceptive activities of pregabalin may also be mediated through interactions with the descending noradrenergic and serotonergic pathways. Pharmacokinetics: 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 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 bioavailability.
Distribution: 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.
Metabolism: Pregabalin undergoes negligible metabolism in humans. The approximately 98% of the pregabalin 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. Pregabalin was no indication of racemisation of pregabalin S-enantiomer to the R-enantiomer.
Elimination: Pregabalin 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.
Dosage adjustment in patients with reduced renal function or undergoing hemodialysis is necessary.
Linearity/Non-linearity: Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (<20%). Multiple-dose pharmacokinetic are predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.
Pharmacokinetics in special patient group: Renal impairment: Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (following a 4-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 following hemodialysis is necessary.
Hepatic impairment: No specific pharmacokinetic studies were carried out in patients with impaired liver function. 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 (over 65 years of age): Pregabalin clearance tends to decrease with increasing age. The 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.
Breast-feeding mothers: Lactation had little to no influence on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk with average steady-state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose.

Neuropathic pain: Pregabalin is indicated for the treatment of central and peripheral neuropathic pain in adults which includes diabetic peripheral neuropathy and post-herpetic neuralgia.
Epilepsy: Pregabalin is indicated as adjunctive therapy for adult patients with partial seizure with or without secondary generalization.
Generalized Anxiety Disorder: Pregabalin is indicated for the treatment of Generalized Anxiety Disorder in adults.
Fibromyalgia: Pregabalin is indicated for the management of fibromyalgia.

Recommended Dose: Recommended Dose between 150-600 mg/day given either two or three divided doses. Pregabalin may be taken with or without food.
Neuropathic pain: Pregabalin treatment can be started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg/day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg/day after an additional 7-day interval.
Epilepsy: Pregabalin treatment can be started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg/day after 1 week.
The maximum dosage of 600 mg/day may be achieved after an additional week.
Generalized Anxiety Disorder: The dose range is 150 to 600 mg/day given as two or three divided doses. The need for treatment should be reassessed regularly.
Pregabalin treatment can be started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg/day after 1 week. Following an additional week the dosage may be increased to 450 mg/day. The maximum dosage of 600 mg/day may be achieved after an additional week.
Fibromyalgia: The usual dose range for most patients is 300 to 450 mg/day given in two divided doses. Some patients may derive additional benefit at 600 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). If needed, in some patients, based on individual patient response and tolerability, the dosage may be increased to maximum dosage of 600 mg/day after an additional week.
Discontinuation of pregabalin: If pregabalin has to be discontinued, it is recommended this should be gradually over a minimum of 1 week.
Patients with renal impairment: Dosage reduction in patients with compromised renal function must be individualized according to creatinine clearance (Clcr), as indicated in Table 1 determined using the following formula: See Equation.

Click on icon to see table/diagram/image

For patients receiving hemodialysis, the pregabalin daily dose should be adjusted based on renal function. ln addition to the daily dose, a supplementary dose should be given immediately following every 4-hour hemodialysis treatment. (See Table 1.)

Click on icon to see table/diagram/image

Use in patients with hepatic impairment: No dosage adjustment is required for patients with hepatic impairment.
Use in children and adolescents (12 to 17 years of age): The safety and effectiveness of pregabalin in pediatric patients below the age of 12 years and adolescents has not been established.
The use in children is not recommended.
Use in the elderly (over 65 years of age): Elderly patients may require a dose reduction of pregabalin due to a decreased renal function.
Mode of Administration: Take Larik 75 capsule with or without meal. When discontinuing, taper off gradually over at least 1 week.

In overdoses up to 15 g, no unexpected adverse effects were reported. There is no specific antidote for pregabalin. Treatment of pregabalin overdose should be symptomatic and supportive treatment.

Larik 75 capsule is contraindicated in patients who have demonstrated hypersensitivity to pregabalin or to any of the excipients.

(Based on the ministry of Public Health Announcement): The drug may cause drowsiness, do not drive a car or operate machinery, or drink alcoholic beverages while taking the drug.
The drug may cause hematologic disorder.
Do not use the drug while pregnant because it may cause teratogenesis.
Use the drug with caution in patients with liver and kidney disease.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycemic medications.
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.
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 post-marketing 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 medication.
In the post-marketing experience, transient visual blurring and other changes in visual acuity have been reported in patients treated with pregabalin. Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.
There are insufficient data for the withdrawal of concomitant antiepileptic medical products, once seizure control with pregabalin in the add-on situation has been reached, in order to reach monotherapy on pregabalin.
After discontinuation of short-term and long-term treatment with pregabalin, withdrawal symptoms have been observed in some patients. The following events have been mentioned: insomnia, headache, nausea, anxiety, hyperhidrosis and diarrhea.
Pregabalin is not known to be active at receptor sites associated with drugs of abuse. Cases of misuse and abuse have been reported in the post marketing database. As with any CNS active drug, carefully evaluated patients for history of drug abuse and observe them for signs of pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).
Although the effects of discontinuation on the reversibility of renal failure have not been systematically studied, improved renal function following discontinuation or dose reduction of pregabalin has been reported.
Although there has been no causal relationship identified between exposure to pregabalin and congestive heart failure. There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Because there are limited data on severe congestive heart failure patients, pregabalin should be used with caution in these patients.
Pregabalin may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medication affects their ability to perform these activities.

Pregnancy: There are no adequate data on the use of pregabalin in women.
Studies in animals have shown reproductive toxicity. The potential risk to human is unknown. Therefore, pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. Effective contraception must be used in women of child-bearing potential.
Lactation: Pregabalin is excreted in the milk of lactation women. As the safety of pregabalin in infants is not known, breast-feeding or to discontinue from pregabalin therapy taking into account the benefit of breast-feeding for the child and benefit of therapy for the woman.

(Based on Lyrica): The pregabalin clinical program involved over 12000 patients who were exposed to pregabalin, of whom over 7000 were in double-blind placebo control 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 14% 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. Selected adverse drug reactions that were treatment related in the pooled analysis of clinical trials are listed in the table as follows by System Organ Class (SOC). The frequency of these term has been based on all-causality adverse drug reactions in the clinical trial data set (very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100) and rare (<1/1000)).
The adverse reactions listed may also be associated with the underlying disease and/or concomitant medications. (See Table 2.)

Click on icon to see table/diagram/image

The following adverse drug reactions were reported during POST-MARKETING SURVEILLANCE: Immune system disorder: Uncommon: Hypersensitivity; Rare: Angioedema, allergic reaction.
Nervous system disorders: Very Common: Headache; Uncommon: Loss of consciousness, mental impairment.
Eye disorder: Rare: Keratitis*.
Cardiac disorder: Rare: Congestive heart failure.
Respiratory, thoracic and mediastinal disorders: Rare: Pulmonary oedema*.
Gastrointestinal disorders: Common: Nausea, diarrhea; Rare: Swollen tongue.
Skin and subcutaneous tissue disorders: Uncommon: Face swelling, pruritus.
Renal and urinary disorders: Rare: Urinary retention.
Reproductive system and breast disorders: Rare: gynaecomastia*.
General disorders and administration site conditions: Uncommon: Malaise.
*Adverse drug reaction frequency estimated using "The Rule of 3".

Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in human (<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.
Accordingly, in in vivo studies no clinical relevant pharmacokinetic interaction 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.
Co-administration of pregabalin with oral contraceptive norethisterone and/or ethinyl estradiol does not influence the steady-state pharmacokinetics of either substance.
Pregabalin may not 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. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.
In the post-marketing experience, there are reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications. There are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics.
No specific pharmacodynamic interaction studies were conducted in elderly volunteers.

Store at room temperature below 30°C.

Anticonvulsants / Drugs for Neuropathic Pain

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

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