bayer primobolan depot

Channels of the presynaptic membranes of neurons, inhibiting the excess release of glutamate bayer primobolan depot and associated with the latest distribution of effector impulses.
Lamotrigine is rapidly and completely absorbed from the intestines, almost without being first-pass metabolism of the first pass. Maximum plasma concentration is reached after about 2.5 hours after ingestion. Time to maximum concentration increases slightly after ingestion, but the degree of absorption is unchanged.There is considerable inter-individual fluctuations in the maximum concentration in an equilibrium state, but with occasional variations in each individual patient.Plasma protein binding is approximately . The bayer primobolan depot volume of distribution is. It is metabolized to the glucuronide, which are excreted in the urine . The clearance half-life, and do not depend on the dose. The half-life in adults is an average of 24-35 hours. In patients with Gilbert’s syndrome was observed decrease in clearance of the drug by, which, however, did not go beyond the normal range for the general population. On the half-life of lamotrigine is greatly affected by drugs taken together (see. “Interaction with other medicinal products”).

In children, the clearance of lamotrigine in the calculation of the body mass is higher than in adults (highest in children under 5 years). The half-life is usually shorter than that of adults. Its average value is equal to 7 hours, while the appointment of drugs that stimulate glucuronidation (phenytoin and carbamazepine) and bayer primobolan depot rises to an average of 45-50 hours, with a joint appointment with valproate (see. “Assigning and dose mode”, “Interaction with other drugs “).
no clinically significant differences in the clearance of lamotrigine in elderly patients compared to younger patients are not detected.
with a significant decrease in kidney function may need to reduce the dose of lamotrigine.
The doses of lamotrigine should be reduced in patients with moderate and severe hepatic insufficiency.

Indications

 

  • as adjunctive or monotherapy bayer primobolan depot epilepsy (partial and generalized seizures, including tonic-clonic seizures and seizures in the syndrome of Lennox -Gasto) in adults and children older than 12 years;
  • as adjunctive therapy epilepsy (partial and generalized seizures, including tonic-clonic seizures and seizures in the syndrome of Lennox -Gasto) in children from 3 to 12 years. After reaching epilepsy control against the background of a combination therapy, concomitant AEDs may be canceled and continued receiving lamotrigine as monotherapy;
  • Monotherapy of typical absence seizures.

Contraindications

Hypersensitivity to any component bayer primobolan depot of the drug, children under 3 years of age, pregnancy and lactation.

With caution : renal insufficiency.

Dosing and Administration

Inside. Because of the risk of rash should not exceed the initial dose and increase the dose recommended by the regime. If more precise dosing, such as part of complex therapy in children, used dosage forms containing lamotrigine in smaller dosages.

Epilepsy Monotherapy in adults and children over 12 years. The initial dose of 25 mg once a day for 2 weeks, followed bayer primobolan depot by increasing doses up to 50 mg once a day for 2 weeks. Thereafter, the dosage is increased by 50-100 mg every 1-2 weeks until the optimum therapeutic effect. Usually, a maintenance dose of 100-200 mg per day in one or two steps. Some patients require up to 500 mg / day. Additional therapy in adults and children over 12 years. In patients receiving valproate in combination with or without other AEDs them, the initial dose is 25 mg every other day for 2 weeks later – on 25 mg once a day for 2 weeks. Then, the dose should be increased by up to 25-50 mg / day every 1-2 weeks until the optimal therapeutic effect is achieved. Usually, a maintenance dose of 100-200 mg / day in one or two steps. In patients receiving concomitant therapy with AEDs or other drugs that stimulate lamotrigine glucuronidation (in combination with other AEDs or without (except valproate)), the initial dose 50 mg once a day for 2 weeks later – 100 mg / day in two divided doses for 2 weeks. Then, the maximum dosage is increased by 100 mg every 1-2 weeks until the optimum therapeutic effect. Usually, a maintenance dose of 200-400 mg per day in two doses. Some patients may require up to 700 mg / day. Patients who take oxcarbazepine in combination with any other inducers or inhibitors of glucuronidation or no lamotrigine them, the initial dose is 25 mg once a day for 2 weeks later – 50 mg / day at once in 2 weeks bayer primobolan depot. Then increase the maximum dose of 50-100 mg every 1-2 weeks until the optimum therapeutic effect. Usually, a maintenance dose of 100-200 mg per day in one or two steps. Monotherapy in children 3 to 12 years. The initial dose of lamotrigine in patients with typical absence seizures of 0.3 mg / kg / day in single or two doses for 2 weeks, followed by increasing doses up to 0.6 mg / kg / day in one or two stages over two weeks. Then increase the maximum dose of 0.6 mg / kg every 1-2 weeks until the optimum therapeutic effect. Usually, the maintenance dose is between 1 and 15 mg / kg / day in one or two steps, although some patients require higher doses. Adjunctive therapy in children aged 3 to 12 years. The children taking valproate in combination with other AEDs or without an initial dose of 0.15 mg / kg body weight once a day for 2 weeks later – 0.3 mg / kg per day at once in 2 weeks. Then, the dose can be increased to 0.3 mg / kg body weight every 1-2 weeks until the optimum therapeutic effect. The usual maintenance dose is 5.1 mg / kg per day in one or two steps. The maximum daily dose – 200 mg. Patients receiving concomitant therapy as a probe, or other drugs that stimulate lamotrigine glucuronidation (in combination with other AEDs or without (except valproate)), an initial dose of 0.6 mg / kg per day in 2 hours for 2 weeks later – 1.2 mg / kg / day. in two doses for 2 weeks. Then, the dose is increased by up to 1.2 mg / kg / day every 1-2 weeks until the optimum therapeutic effect. The usual maintenance dose is 5-15 mg / kg per day in two stages with a maximum dose of 400 mg / day. Patients receiving oxcarbazepine without any other inducers or inhibitors of lamotrigine glucuronidation, the initial dose of lamotrigine is 0.3 mg / kg / day in one or two stages over two weeks later – 0.6 mg / kg / day in one or two stages over two weeks. Then, the dose is increased by up to 0.6 mg / kg every 1-2 weeks until the optimum therapeutic effect is attained. Typically, a maintenance dose is 1-10 mg / kg / day in one or two steps. The maximum dose is 200 mg / day. It is likely that children aged 3 to 6 years old will require the highest maintenance dose.

 

Bipolar disorders in adults
should be followed transition dosage regimen, which includes increasing during 6 weeks dose of lamotrigine to maintenance stabilizing doses then, if indicated, it is possible to cancel other psychotropic and / or probe.
Target stabilizing dose varies depending on the clinical effect. a) Adjunctive therapy in patients taking lamotrigine glucuronidation inhibitors (e.g., valproate). The initial dose of lamotrigine is 25 mg every other day for two weeks, followed by 25 mg once a day for 2 weeks. The dose should be increased to 50 mg (1-2 doses) for 5 weeks. Typically, the target dose of 100 mg / day (1-2 doses). The maximum daily dose – 200 mg b) Adjunctive therapy in patients concurrently taking drugs that stimulate the glucuronidation of lamotrigine and not taking inhibitors of glucuronidation of lamotrigine (eg valproate). This mode should be used with phenytoin, carbamazepine, phenobarbital, primidone or other inducers glucuronidation of lamotrigine. The initial dose of lamotrigine is 50 mg once a day for 2 weeks followed by 100 mg per day in two divided doses for 2 weeks. At the 5th week of the dose should be increased to 200 mg per day in two doses. At the 6-th week, the dose may be increased to 300 mg a day, but usually, the target dose is 400 mg per day (two doses) and assigned starting at 7 weeks of treatment. C) Monotherapy lamotrigine or adjunctive therapy in patients taking drugs lithium, bupropion, olanzapine, oxcarbazepine, or other drugs which do not have a significant inducing or inhibitory effect on glucuronidation of lamotrigine. The initial dose of lamotrigine is 25 mg once a day for 2 weeks followed by 50 mg per day (one or 2 doses) for 2 weeks. The dose should be increased to 100 mg a day for 5 weeks. Typically, the target dose is 200 mg per day (1 or 2 divided doses). After reaching the target supports the stabilizing dose of other psychotropic medications may be removed. If necessary, the dose may be increased to 400 mg / day. A) Therapy of lamotrigine after the abolition of additional therapy inhibitors of glucuronidation of lamotrigine (eg valproate): immediately after the abolition of valproate, stabilizing the initial dose lamotrigine doubles and maintained at this level. b) after cancellation of lamotrigine therapy adjunctive therapy inducers of lamotrigine glucuronidation depending on original maintenance dose. this mode should be used when using phenytoin, carbamazepine, phenobarbital, primidone or other inducers of lamotrigine glucuronidation. Lamotrigine dose is gradually reduced over 3 weeks after discontinuation of inductors glucuronidation. C) Therapy of lamotrigine after the abolition of concomitant psychotropic or AED, no significant pharmacokinetic interaction with lamotrigine (eg lithium drugs, bupropion, olanzapine, oxcarbazepine). During the cancellation related to lamotrigine medications It should be maintained target dose of lamotrigine reached in the process of raising mode. d) Adjustment of lamotrigine daily dose following the addition of other drugs. The following recommendations (table 1) can be given on the basis of studies on the interaction of drugs.

 

Reappointment
The more time has passed after the last dose, the more caution should be increased to a maintenance dose. If the time after discontinuation of more than 5 half-lives, the lamotrigine dose should be increased to support, under the relevant scheme. It is not recommended to renew the appointment of lamotrigine patients who discontinued the drug due to the occurrence of rash, unless the potential benefit from the appointment of the drug, significantly, does not exceed the risk.

General dosing recommendations for lamotrigine in special patient groups

Women taking hormonal contraceptives a) Appointment of lamotrigine to patients already receiving hormonal contraceptives: no need for a correction recommended regimens increase lamotrigine dose. B) The appointment of hormonal contraceptives to patients already receiving maintenance doses of lamotrigine and NOT receiving inductors glucuronidation of lamotrigine: you may need to increase the maintenance dose lamotrigine, but not more than 2-fold, depending on the individual clinical response. c) Stopping hormonal contraceptives patients already receiving maintenance doses of lamotrigine and nOT receiving inductors glucuronidation of lamotrigine: you may need to decrease the dose of lamotrigine to 2 times, depending on the individual clinical effect.

 

Elderly patients (over 65)
Changes in recruitment scheme doses are required.

Abnormal liver function
An initial, growing and maintenance dose should be reduced by approximately 50% and 75% in patients with moderate (stage B) and severe (stage C) degrees of hepatic impairment, respectively. Growing and maintenance doses should be adjusted depending on clinical response.

Renal impairment
Patients with severely reduced renal function may be recommended maintenance dose reduction.

Side effect

Violations of the skin and subcutaneous tissue: skin rash. Rash, mainly maculopapular, usually appears during the first 8 weeks of the start of therapy and disappears after discontinuation bayer primobolan depot of the drug. There are reports of rare cases of severe, potentially life-threatening skin lesions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome). Although in most cases to remove the drug occurred regression of symptoms, some patients were permanent scars on the skin; known single cases of fatal lesions. Largely increased risk of dermatological complications associated with impaired recommended mode titration doses (exceeding the initial dose or exceeding the rate of increase of doses), as well as with an increase in half-life of lamotrigine when co-administered with drugs valproic acid (see “Dosage and administration”.; “Interactions with other medicinal products”). Due to the fact that almost all cases of skin rashes occurred within the first 8 weeks of treatment with lamotrigine can not be considered duration of therapy as a risk prediction tool of dermatological complications. Development of the rash may also be seen as a manifestation of a hypersensitivity syndrome. In children, the risk of serious skin rashes is higher than that of adults. The blood and lymphatic system: neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, aplastic anemia, agranulocytosis. Hematologic abnormalities may or may not be associated with a syndrome of hypersensitivity. Violations of the immune system: Hypersensitivity syndrome (including symptoms such as skin rash, fever, lymphadenopathy, swelling of the face, blood disorders and liver function, dissiminirovannoy intravascular syndrome coagulation (DIC), multiple organ disorders). The early manifestations of hypersensitivity (eg fever, lymphadenopathy) may occur even in the absence of clear signs of a rash. With the development of these symptoms, the patient should be immediately examined by a doctor and, if not installed another cause of symptoms, lamotrigine should be abolished. Nervous system disorders: headache, dizziness, nystagmus, tremor, ataxia, drowsiness, insomnia, aggressiveness, irritability, tics, hallucinations, confusion, agitation, unsteadiness, movement disorders, worsening of Parkinson’s disease, extrapyramidal disorder, choreoathetosis, increase in the frequency of seizures. Visual impairment:diplopia, blurred vision, conjunctivitis. Gastrointestinal disorders: nausea, diarrhea. Hepato-biliary disorders : increased levels of liver enzymes, abnormal liver function, hepatic failure. Violations of the liver usually develop in conjunction with symptoms of hyperactivity, but in a few cases were noted in the absence of overt signs of hypersensitivity. Violations of the muscle and connective tissue: lupus-like syndrome, arthralgia. General Disorders: fatigue, pain in the body and limbs.

Overdose

It reported on single dose of doses in excess of the maximum therapeutic 10-20 times. Overdose manifested symptoms including nystagmus, ataxia, impaired consciousness and coma.
Treatment: gastric lavage, hospitalization and symptomatic therapy.

special instructions

Skin rash
in children initial manifestations of rash can be mistaken for an infection, so doctors must take into account the possibility of the reaction of children to the drug manifested development of rash and fever during the first 8 weeks of therapy.
When a rash all patients (adults and children) should be rapidly examined by a doctor. Acceptance of lamotrigine should be discontinued immediately except in cases where it is obvious that the development of the rash is not related to the drug intake. It is not recommended to resume receiving lamotrigine when his previous appointment was canceled due to the development of a skin reaction. DihydrofolateLamotrigine is a weak inhibitor of dihydrofolate, so it is likely the influence of the drug on the metabolism of folate in its long-term appointment. However, it was shown that lamotrigine did not cause significant changes in hemoglobin concentration, mean corpuscular volume, at a concentration of folate erythrocytes destination duration serum preparation to 1 year or reduced folate bayer primobolan depot concentration in erythrocytes in the appointment of lamotrigine for up to 5 years. Epilepsy Abrupt withdrawal receiving lamotrigine as and other AEDs, can provoke seizures develop. If abrupt discontinuation of therapy is not a safety requirement (for example, the appearance of the rash), the dose of lamotrigine should be reduced gradually over a period of 2 weeks. There are reports in the literature that severe convulsive seizures including status epilepticus may lead to rhabdomyolysis, multiple organ disorders and disseminated intravascular coagulation, sometimes with fatal outcome. Such cases were observed in the treatment of patients with lamotrigine. Bipolar Disorder The possibility of suicide attempt is a characteristic feature of bipolar disorder, therefore the treatment of such patients should be under close supervision.

 

Interactions with other drugs

The average half-life is reduced to approximately 14 hours, while the appointment of drugs that stimulate glucuronidation, such as carbamazepine and phenytoin and is increased to an average of 70 hours at a joint appointment with valproate.
Uridine diphosphate (UDP) glucuronyl is the main metabolizing enzyme lamotrigine. No Information about the ability of lamotrigine to cause clinically significant inhibition or induction of oxidative liver enzymes. In this regard, the interaction between lamotrigine and drugs metabolized by cytochrome P450 enzyme system, it is unlikely. Lamotrigine can stimulate its own metabolism but the effect is moderate and does not have clinically significant consequences.
Valproate has a strong inhibitory effect on glucuronidation of lamotrigine.
Carbamazepine, phenytoin, primidone, phenobarbital, rifampin combined preparation etiniloestradiol / levonorgestrel – have a stimulating effect on the glucuronidation of lamotrigine. The influence of other oral contraceptives and hormone replacement therapy has not been studied, though they may have a similar effect on the pharmacokinetic parameters of lamotrigine.
Lithium drugs, bupropion, olanzapine, oxcarbazepine – no significant inhibitory effect on glucuronidation of lamotrigine.

Interactions with AEDs
Valproate, which inhibits the glucuronidation of lamotrigine, reduces the rate of its metabolism and lengthens its average half-life of almost 2 times.
Certain antiepileptic drugs (such as phenytoin, carbamazepine, fenabarbital and primidone) which stimulate the system of the liver metabolizing enzymes accelerate the glucuronidation of lamotrigine and its metabolism. It reported on the development of adverse effects to the central nervous system, include dizziness, ataxia, diplopia, blurred vision and nausea in patients taking carbamazepine who started on the background of lamotrigine therapy. These symptoms usually resolve after reduction of the dose of carbamazepine. A similar effect was observed in the appointment of lamotrigine and oxcarbazepine in healthy volunteers, the result of reducing the dose has not been investigated.
Lamotrigine does not displace other AEDs from their association with plasma proteins.
When concomitant administration of lamotrigine 200 mg and oxcarbazepine at a dose of 1200 mg or oxcarbazepine and no lamotrigine not violate the metabolism of each other.

Interactions involving other psychoactive drugs
lamotrigine at 100 mg / day does not cause disturbances pharmacokinetics anhydrous gluconate lithium (2 g, 2 times a day for 6 days) when coadministered.
Multiple assignment bupropion inside had no statistically significant effect on the pharmacokinetics of a single dose of lamotrigine and causes a slight increase in the AUC (area under the curve, “concentration-time”) of lamotrigine glucuronide.
Alanzapin 15 mg reduces AUC and Cmax of lamotrigine by an average of 24% and 20% respectively. Changes of this level is not usually require clinical significance. Lamotrigine at 200 mg did not alter alanzapina kinetics.
Inhibition of lamotrigine amitriptyline, bupropion, clonazepam, fluoxetine, haloperidol or lorazepam has bayer primobolan depot minimal effect on the formation of the primary metabolite of lamotrigine, 2-N-glucuronide. The study of metabolism bufuralola microsomal liver enzymes isolated from human, allows us to conclude that lamotrigine does not reduce the clearance of drugs eliminated predominantly isoenzymes CYP2D6. The results of in vitro studies also suggest that clozapine, phenelzine, risperidone, sertraline and trazodone are unlikely to affect the clearance of lamotrigine.

Interactions with hormonal contraceptives
Effect of hormonal contraceptives on the pharmacokinetics of lamotrigine.
Receiving combined oral contraceptive containing 30 .mu.g etiniloestradiola and 150 .mu.g levonorgestrel is approximately two-fold increase in clearance of lamotrigine (after oral administration), which leads to a decrease in AUC and Cmax of lamotrigine by an average of 52 % and 39% respectively. During the week of receiving the free active drug, there is an increase plasma concentrations of lamotrigine, wherein the concentration of lamotrigine, measured at the end of this week before administering the next dose, the average is 2 times higher than that in the active therapy.

The influence on the pharmacokinetics of lamotrigine hormonal contraceptives
equilibrium concentrations of lamotrigine Period 300 mg did not affect the pharmacokinetics etiniloestradiola – component of combined oral contraceptives. Observed slight increase in the clearance of the second component of oral contraceptives – levonorgestrel that resulted in lower Cmax and AUC of levonorgestrel at 19% and 12% respectively. Measurement of serum FSH, LH and oestradiol during the study showed a slight decrease in suppression of ovarian hormonal activity in some women, although measurement of plasma progesterone, none of the 16 women showed no hormonal evidence of ovulation.Effect of moderate increase in levonorgestrel clearance and changes in plasma levels of FSH and LH on ovarian ovulatory activity is not found. Interactions with other drugs
Rifampicin increases the clearance of lamotrigine and reduces its half-life due to the stimulation of hepatic enzymes bayer primobolan depot responsible for glucuronidation. Patients receiving rifampicin as co-therapy, the appointment of lamotrigine treatment must comply with the scheme recommended by a joint appointment of lamotrigine and means of stimulating glucuronidation.