Convalis, 300 mg capsules 50 pcs

Pharmacotherapeutic group: anti-epileptic drug.

ATX code: N03AX12.

Pharmacological Properties

Pharmacodynamics

The chemical structure of gabapentin is similar to that of the neurotransmitter GABA (gamma-aminobutyric acid), but its mechanism of action differs from other active agents that interact with GABA synapses, such as valproates, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA reuptake inhibitors, GABA agonists and GABA prodrugs. In in vitro studies with the radioisotope-labeled gabapentin in the rat brain, new regions of binding of the drug to proteins were found, including in the neocortex and hippocampus, which may be relevant to the anticonvulsant and analgesic activity of gabapentin and its derivatives. The binding site of gabapentin was found to be the α-2-δ (alpha-2-delta) subunit of potential-dependent calcium channels.

In clinically relevant concentrations, gabapentin does not bind to other common drug and neurotransmitter receptors present in the brain, including GABA_A, GABA_B, benzodiazepine, glutamate, glycine and N-methyl-D-aspartate receptors.

Gabapentin under in vitro conditions does not interact with sodium channels, which distinguishes it from phenytoin and carbamazepine. In a number of in vitro test systems the use of gabapentin resulted in a partial reduction in response to the glutamate agonist N-methyl-D-aspartate (NMDA), but only at concentrations greater than 100 μmol/L, which is not achievable in in vivo conditions. Under in vitro conditions, the use of gabapentin results in a slight decrease in monoamine neurotransmitter release.

The exact mechanism of action of gabapentin is unknown.

Pharmacokinetics

absorption

. After oral administration, the maximum plasma concentration of gabapentin is reached within 2-3 hours. Bioavailability of gabapentin tends to decrease with increasing dose of the drug. Absolute bioavailability when taking 300 mg capsules is approximately 60%. Foods, including those with high fat content, have no clinically significant effect on the pharmacokinetic parameters of gabapentin.

The pharmacokinetics of gabapentin do not change with repeated administration of the drug.

Distribution

Gabapentin does not bind to plasma proteins and its volume of distribution is 57.7 L. In patients with epilepsy, the concentration of gabapentin in the cerebrospinal fluid (CSF) is approximately 20% of the minimum equilibrium plasma concentration. Gabapentin is excreted in breast milk.

Biotransformation

There are no data on the metabolism of gabapentin in humans. Gabapentin does not cause induction of nonspecific liver oxidases responsible for drug metabolism.

Elimation

Gabapentin is excreted unchanged exclusively by renal excretion. The half-life of gabapentin is independent of the dose taken and averages 5 to 7 hours.

In elderly patients and patients with impaired renal function the blood plasma clearance of gabapentin is decreased. The elimination constant, plasma clearance and renal clearance of gabapentin are directly proportional to creatinine clearance.

Gabapentin is eliminated from blood plasma by hemodialysis. Patients with impaired renal function or who are on hemodialysis are recommended to adjust the dose of the drug (see section “Dosage and administration”).

Linearity/nonlinearity of pharmacokinetic parameters

The bioavailability of gabapentin decreases with increasing dose taken, resulting in non-linearity of pharmacokinetic parameters that include bioavailability (F), such as Ae%, CL/F, Vd/F. Elimination pharmacokinetics (parameters not including F, such as CLr and T_1/2) are better described by a linear model. Equilibrium plasma concentrations of gabapentin are predictable based on single administration kinetics data.

Indications

Active ingredient

Composition

active ingredient: gabapentin – 300.0 mg;

excipients: lactose monohydrate – 66.0 mg, corn starch pregelatinized – 30.0 mg, talc – 3.0 mg, magnesium stearate – 1.0 mg.

The weight of the capsule contents is 400.0 mg.

Capsule shell composition

Solid gelatin capsules № 0 – 96.0 mg.

Capsule and lid: titanium dioxide (E 171) – 2.0000%, iron oxide yellow dye (E 172) – 0.6286%, gelatin – up to 100%.

The total weight of the capsule with the contents – 496.0 mg.

How to take, the dosage

Convalis® is administered orally regardless of meals. If it is necessary to reduce the dose, discontinue the drug or replace it with an alternative remedy, this should be done gradually over at least one week.

Neuropathic pain in adults

The starting dose is 900 mg/day in three equal doses; if necessary, depending on the effect, the dose is gradually increased to a maximum of 3600 mg/day. Treatment may begin immediately with a dose of 900 mg/day (300 mg three times daily) or the dose may be increased gradually to 900 mg daily for the first 3 days according to the following schedule:

Day 1: 300 mg of the drug once daily;

Day 2: 300 mg of the drug 2 times daily;

Day 3: 300 mg of the drug 3 times daily.

Parcial seizures

Epilepsy usually requires long-term treatment. The dose of the drug in this case is determined by the treating physician depending on individual tolerance and effectiveness of the drug.

Adults and children over 12 years of age:the effective dose is 900 to 3600 mg/day. Therapy may be started with a dose of 300 mg 3 times daily on the first day or increased gradually to 900 mg according to the scheme described above (see subsection “Neuropathic pain in adults”). Subsequently, the dose may be increased to a maximum of 3600 mg/day (divided into 3 equal doses). Good tolerability of the drug in doses up to 4800 mg/day has been noted. The maximum interval between doses in triple dosing should not exceed 12 hours in order to avoid recurrence of seizures.

Patients in severe condition

In patients in severe condition, such as underweight, after organ transplantation, etc., the dose should be increased more slowly, either using lower doses or longer intervals before increasing the dose.

Application in elderly patients (over 65 years of age)

Dose adjustment may be required in elderly patients due to age-related reduction in renal function (see Table 1 for more information). Sleepiness, peripheral edema, and asthenia may be more common in elderly patients.

Recommendations for patients on hemodialysis

Patients on hemodialysis who have not previously taken gabapentin are advised to administer the drug at a saturation dose of 300 mg and then use 300 mg after every 4 hours of hemodialysis.

For patients with reduced renal function on dialysis, the maintenance dose of gabapentin should be adjusted according to the recommendations in Table 1. In addition to maintenance therapy, administration of 300 mg of gabapentin after each 4-hour hemodialysis session is recommended.

Interaction

There have been reports of spontaneous cases, as well as information from the literature, of possible respiratory depression and/or sedation symptoms associated with the administration of gabapentin and opioid analgesics. In some of these cases, the authors attributed these symptoms to concomitant use of gabapentin and opioids, particularly in older patients.

When gabapentin 600 mg was used 2 hours after administration of morphine in the form of 60 mg sustained-release capsules, an increase of 44 % in average AUC of gabapentin was noted in comparison with gabapentin monotherapy, which is associated with increase of pain threshold (cold pressor test). The clinical significance of this change has not been established, and the pharmacokinetic characteristics of morphine were not altered. Side effects of morphine combined with gabapentin did not differ from those of morphine combined with placebo. The degree of interaction of these drugs in other doses is unknown.

No interactions have been noted between gabapentin and phenobarbital, phenytoin, valproic acid and carbamazepine. Equilibrium pharmacokinetics of gabapentin are similar in healthy subjects and patients receiving other anticonvulsants.

The concomitant use of gabapentin with oral contraceptives containing norethisterone and/or ethinylestradiol is not accompanied by changes in pharmacokinetics of both components.

The concomitant use of gabapentin with antacids containing aluminum and magnesium is accompanied by a decrease in the bioavailability of gabapentin by approximately 24% (see section “Special Precautions”).

Probenecid does not affect renal excretion of gabapentin.

The slight decrease (14%) in renal excretion of gabapentin when concomitantly taking cimetidine is probably not clinically relevant.

Concomitant use of naproxen (250 mg) and gabapentin (125 mg) showed increased absorption of gabapentin from 12% to 15%. Gabapentin has no effect on pharmacokinetic parameters of naproxen. The indicated drug doses are less than the minimum therapeutic doses. Concomitant use of these drugs in high doses has not been studied.

Special Instructions

The antiepileptic drugs, including gabapentin, may increase the risk of suicidal thoughts or behaviors. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs demonstrated a small increase in the risk of suicidal thoughts and behaviors. The mechanism for the increased risk of suicidal ideation is unknown, but it cannot be ruled out for gabapentin.

Patients receiving these medications should therefore be closely monitored for the onset or worsening of depression, the occurrence of suicidal thoughts or behaviors, and any changes in behavior. Patients, or their caregivers, should see a physician if suicidal thoughts or behaviors appear.

Acute pancreatitis

If acute pancreatitis develops while taking gabapentin, the possibility of withdrawing the drug should be evaluated.

Convulsions (withdrawal syndrome)

While withdrawal syndrome accompanied by seizures has not been noted with gabapentin treatment, abrupt discontinuation of anticonvulsant therapy in patients with epilepsy may provoke epileptic status.

As with other antiepileptic drugs, an increase in the frequency of seizures or the appearance of another type of seizures may be observed with gabapentin.

As with other anticonvulsants, attempts to withdraw all concomitant antiepileptic medications to initiate gabapentin monotherapy in patients refractory to treatment in patients taking multiple anticonvulsants have generally not been successful.

Gabapentin is thought to be ineffective in primary generalized seizures, such as absences, and may even exacerbate such seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizures, including absences.

Elderly patients

There have been no systematic studies of patients aged 65 years or older taking gabapentin. In a double-blind study of gabapentin use for neuropathic pain, a higher incidence of somnolence, peripheral edema, and asthenia was observed in patients aged 65 years or older compared with patients younger than 65 years. Excluding these results, clinical examination of this group of patients showed that their side effect profile was not different from the others.

Children

The effects of long-term therapy (more than 36 weeks) with gabapentin on learning ability, intelligence, and child development are not well understood. The ratio of possible risk to benefit of prescribing long-term therapy should be evaluated.

Misuse and dependence

The post-registration observational database has reported cases of drug abuse and dependence. As with any CNS-affecting drug, physicians should carefully review patients’ history of drug abuse and monitor patients for possible signs of gabapentin abuse (e.g., seeking the drug unreasonably, developing resistance to gabapentin therapy, unreasonably increasing the dose of the drug).

DRESSsyndrome

. Cases of severe life-threatening hypersensitivity reactions, such as drug rash with associated eosinophilia and systemic symptoms, have been reported with antiepileptic drugs, including gabapentin. It should be remembered that early signs of hypersensitivity reactions, such as increased body temperature, lymphadenopathy, may develop even in the absence of a skin rash. If such symptoms occur, immediate examination of the patient is necessary. If no other cause other than gabapentin has been found, use of the drug should be stopped.

Anaphylaxis

The administration of gabapentin may lead to the development of anaphylaxis. The following symptoms and signs were noted in cases of anaphylaxis with gabapentin – difficulty in breathing, swelling of the lips, throat and tongue, also a marked decrease in blood pressure was noted, requiring urgent medical intervention. Patients should be cautioned that if signs or symptoms of anaphylaxis develop, the drug should be stopped and medical attention sought.

Laboratory tests

. False-positive results have been reported with Ames N-Multistix SG® Test Strips when co-administering gabapentin and other anticonvulsants. The more specific sulfosalicylic acid precipitation method is recommended for detection of protein in urine.

Influence on the CNS

In the course of treatment with gabapentin, dizziness and somnolence have been observed, which may increase the likelihood of accidental injury (from a fall). Cases of confusion, loss of consciousness, and impaired mental performance have also been reported in the post-registration period. Therefore, patients should be advised to exercise caution until they are aware of the possible effects of this medication.

In concomitant use with opioid analgesics, increased plasma concentrations of gabapentin may be noted. In this regard, the patient requires close monitoring for signs of CNS depression, such as drowsiness, sedation and respiratory depression. Doses of gabapentin or opioid analgesics should be reduced.

Combined use with antacids

Gabapentin is recommended approximately 2 hours after taking an antacid.

Effects on the ability to operate vehicles and machinery

Patients should not drive vehicles or use potentially dangerous machinery while taking the drug until it is confirmed that there is no adverse effect of the drug on these functions.

Gabapentin affects the CNS and may cause dizziness, drowsiness, confusion, loss of consciousness or other CNS symptoms. Even if mild to moderate, these adverse effects may pose a danger to patients operating vehicles or other machinery. This is particularly likely at the beginning of treatment or after increasing the dose of gabapentin.

Synopsis

Contraindications

WARNING

Renal failure (see “Dosage and administration”).

Side effects

The side effects observed in clinical trials of patients with epilepsy (when using gabapentin as monotherapy or in combination with other anticonvulsants) or neuropathic pain are presented below and categorized by organ system and frequency.

The frequency category was defined as follows: very frequently (≥1/10); frequently (≥1/100 to < 1/10); infrequently (≥1/1000 to < 1/100); rarely (≥1/10000 to < 1/1000); very rarely (< 1/10 000). If the frequency category was different between studies, the side effect was assigned a higher category.

The side effects reported during use of the drug after registration were assigned a frequency category of “unknown” (frequency cannot be calculated from available data).

In each frequency section, side effects are presented in decreasing order of severity.

Infectious and parasitic diseases: very common – viral infections; frequent – pneumonia, respiratory tract infection, urinary tract infection, other infections, otitis media.

Blood and lymphatic system disorders: frequently – leukopenia; not known – thrombocytopenia.

Disorders of the immune system: infrequent – allergic reactions, including urticaria; not known – hypersensitivity, including systemic reactions such as fever, rashes, hepatitis, lymphadenopathy, eosinophilia and others.

Disorders of metabolism and nutrition: often – anorexia, increased appetite.

Mental disorders: often – hostility, confusion, depression, anxiety, nervousness, impaired thinking, emotional lability; not infrequently – mental deterioration; unknown – hallucinations.

Nervous system disorders: very often – somnolence, dizziness, ataxia; frequently – seizures, hyperkinesia, dysarthria, amnesia, tremor, insomnia, headache, sensory disturbances (eg, paresthesia, hypoesthesia), coordination disorders, nystagmus, amplification, weakening or absence of reflexes; frequently – hypokinesia; frequently – loss of consciousness; unknown – other movement disorders (e.g., choreoathetosis, dyskinesia and dystonia).

Visual disorders:often – visual disturbances (such as, amblyopia, diplopia).

Hearing organ and labyrinth disorders: often – vertigo; unknown – tinnitus.

Cardiac disorders: infrequent – palpitations.

Vascular disorders: often – symptoms of vasodilation or arterial hypertension.

Disorders of the respiratory system, thoracic and mediastinal organs: often – shortness of breath, bronchitis, pharyngitis, cough, rhinitis.

Gastrointestinal tract disorders: often – constipation, diarrhea, dry mucous membrane of the mouth or throat, dyspepsia, flatulence, nausea, vomiting, abdominal pain, dental disease, gingivitis; not known – pancreatitis.

Liver and biliary tract disorders: unknown – hepatitis, jaundice.

Skin and subcutaneous tissue disorders: often – facial edema, purpura (most commonly described as bruising from physical trauma), skin rash, acne, itchy skin; unknown – Stevens-Johnson syndrome, angioneurotic edema, erythema multiforme, alopecia, drug-induced skin rash, including eosinophilia and systemic reactions (see. See section “Special Indications”).

Muscular and connective tissue disorders: often – myalgia, arthralgia, back pain, muscle twitching; unknown – rhabdomyolysis, myoclonus.

Renal and urinary tract disorders: unknown – urinary incontinence, acute renal failure.

disorders of the genitals and the mammary gland: often – impotence; unknown – increase in breast volume, gynecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia).

General disorders and disorders at the site of administration: very often – fatigue, fever; frequently – peripheral edema, gait disturbance, asthenia, pain of various localization, general malaise, flu-like syndrome; infrequent – generalized edema; unknown – withdrawal syndrome (the following side effects were most commonly reported: anxiety, insomnia, nausea, pain of various localization and increased sweating), chest pain. There have been cases of sudden unexplained death, which have not been associated with treatment with gabapentin.

Laboratory and instrumental findings: frequently – decreased white blood cell concentration, increased body weight; infrequently – increased alanine aminotransferase activity, aspartate aminotransferase activity and plasma bilirubin concentration, hyperglycemia; rarely – hypoglycemia (mainly in patients with diabetes mellitus); unknown – hyponatremia, increased creatine phosphokinase activity.

Injuries, intoxications and complications of manipulations: often – injuries, fractures, abrasions associated with falls.

There have been reports of the development of acute pancreatitis on therapy with gabapentin. The causal relationship to gabapentin remains unclear (see section “Special Precautions”).

There have been reports of cases of myopathy with increased creatine kinase activity in patients with end-stage renal failure on hemodialysis.

Cases of respiratory tract infection, otitis media, bronchitis and seizures have only been reported in clinical studies. In addition, cases of aggressive behavior and hyperkinesias in children have been reported in clinical studies.

If any of the side effects listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

Pregnancy use

General risk due to epilepsy and antiepileptic drugs

The risk of children born with congenital anomalies to mothers treated with anticonvulsants increases by 2 to 3 times. Cleft lip and palate, cardiovascular malformations, and neural tube defects are the most common. At the same time, taking several anticonvulsants may be associated with a greater risk of malformations than in the case of monotherapy. Therefore, if possible, one of the anticonvulsant drugs should be used. Women of childbearing age, as well as all women who are likely to become pregnant, should be consulted by a qualified specialist. If a woman is planning to become pregnant, the need to continue anticonvulsant therapy should be reassessed. At the same time, anticonvulsants should not be abruptly withdrawn, as this may lead to a recurrence of seizures with severe consequences for the mother and child. In rare cases, developmental delays have been observed in children whose mothers have epilepsy. It is not possible to determine whether the developmental delay is due to genetic or social factors, maternal illness, or anticonvulsant therapy.

Risk due to gabapentin

There are no data on the use of the drug in pregnant women. Toxicity of the drug to the fetus has been shown in animal experiments. No data are available regarding the possible risk in humans. Therefore, gabapentin should be used during pregnancy only if the anticipated benefit to the mother justifies the possible risk to the fetus.

In the cases that have been reported, it is uncertain whether or not the use of gabapentin during pregnancy is associated with an increased risk of malformations, first because of epilepsy itself and second because of the use of other anticonvulsant drugs.

Breastfeeding

Gabapentin is excreted with breast milk and its effects on the breastfed infant are unknown, so while breastfeeding Convalis® should be prescribed only if the benefit to the mother clearly outweighs the risk to the infant.

The effects of gabapentin on fertility have not been noted in animal studies.

Similarities