Convalis^® (Capsules) Instructions for Use

Marketing Authorization Holder

Lekko, CJS (Russia)

Manufactured By

Pharmstandard-Lexredstva OJSC (Russia)

Or

Otisipharm Pro, JSC (Russia)

ATC Code

N03AX12 (Gabapentin)

Active Substance

Gabapentin (Rec.INN registered by WHO)

Dosage Form

Convalis®

Capsules 300 mg: 30, 50, or 100 pcs.

Dosage Form, Packaging, and Composition

Capsules size No. 0, yellow in color; the capsule contents are a crystalline powder of white or yellowish color.

Excipients: lactose monohydrate – 66 mg, corn starch pregelatinized – 30 mg, talc – 3 mg, magnesium stearate – 1 mg.

Mass of capsule contents – 400 mg.
Capsule shell hard gelatin No.0 – 96 mg.
Composition of the capsule shell (body and cap) titanium dioxide (E171) – 2%, iron oxide yellow (E172) – 0.6286%, gelatin – up to 100%.
Total mass of the capsule with contents – 496 mg.

10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (5) – cardboard packs.
10 pcs. – blister packs (10) – cardboard packs.
20 pcs. – blister packs (5) – cardboard packs.

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Analgesics; other analgesics and antipyretics; gabapentinoids

Pharmacological Action

The chemical structure of gabapentin is analogous to the structure of the neurotransmitter GABA, however its mechanism of action differs from other active substances interacting with GABA synapses, such as valproates, barbiturates, benzodiazepines, GABA-transaminase inhibitors, GABA reuptake inhibitors, GABA agonists and GABA prodrugs. In in vitro studies with radioisotope-labeled gabapentin in the rat brain, new areas of drug binding to proteins were discovered, including in the neocortex and hippocampus, which may be related to the anticonvulsant and analgesic activity of gabapentin and its derivatives. It was established that the binding site for gabapentin is the α-2-δ (alpha-2-delta) subunit of voltage-gated calcium channels.

At clinically significant 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 (NMDA) receptors.

Gabapentin does not interact with sodium channels in vitro, which distinguishes it from phenytoin and carbamazepine. In a number of in vitro test systems, the application of gabapentin led to a partial reduction of the response to the NMDA glutamate agonist, but only at concentrations exceeding 100 µmol/L, which is not achievable in vivo. In vitro, the application of gabapentin leads to a slight reduction in the release of monoamine neurotransmitters.

The exact mechanism of action of gabapentin is unknown.

Pharmacokinetics

After oral administration, the C_max of gabapentin in plasma is reached within 2-3 hours. The bioavailability of gabapentin tends to decrease with increasing drug dose. The absolute bioavailability when taking 300 mg capsules is approximately 60%. Food, including high-fat food, does not have a clinically significant effect on the pharmacokinetic parameters of gabapentin. The pharmacokinetics of gabapentin do not change upon repeated administration of this agent. Gabapentin does not bind to plasma proteins, and its V_d is 57.7 L. In patients with epilepsy, the concentration of gabapentin in the cerebrospinal fluid is approximately 20% of the minimum C_ss in plasma. Gabapentin is excreted in breast milk. There are no data on the metabolism of gabapentin in the human body. Gabapentin does not induce non-specific liver oxidases responsible for drug metabolism. Gabapentin is excreted unchanged solely by renal excretion. The T_1/2 of gabapentin is independent of the administered dose and averages from 5 to 7 hours. In elderly individuals and patients with impaired renal function, the plasma clearance of gabapentin is reduced. The elimination constant, plasma clearance and renal clearance of gabapentin are directly proportional to CrCl. Gabapentin is removed from plasma by hemodialysis. Dose adjustment of this agent is recommended for patients with impaired renal function or those undergoing hemodialysis.

The bioavailability of gabapentin decreases with increasing administered dose, which entails nonlinearity of pharmacokinetic parameters that include the bioavailability (F) in their calculation, for example, Ae%, CL/F, V_d/F. Elimination pharmacokinetics (parameters not including F, such as Clr T_1/2) are better described by a linear model. The steady-state plasma concentrations of gabapentin are predictable based on single-dose kinetic data.

Indications

• Treatment of neuropathic pain in adults aged 18 years and older (the efficacy and safety of gabapentin for the treatment of neuropathic pain in patients under 18 years of age have not been established);
• Monotherapy of partial seizures with and without secondary generalization in adults and children aged 12 years and older (the efficacy and safety of gabapentin as monotherapy for partial seizures in children under 12 years of age have not been established).

ICD codes

Dosage Regimen

Orally, regardless of meals. If it is necessary to reduce the dose, discontinue Gabapentin or replace it with an alternative agent, this should be done gradually over a minimum of one week.

Gabapentin is used according to a special regimen.

The initial dose is 900 mg/day in 3 divided equal doses; if necessary, depending on the effect, the dose is gradually increased to a maximum of 3600 mg/day. Good tolerance has been noted at doses up to 4800 mg/day.

Patients with renal failure require dose adjustment.

Adverse Reactions

Infections and infestations very common – viral infections; common – pneumonia, respiratory tract infection, urinary tract infection, other types of infection, otitis media.

Blood and lymphatic system disorders common – leukopenia; unknown – thrombocytopenia.

Immune system disorders uncommon – allergic reactions, including urticaria; unknown – hypersensitivity, including systemic reactions such as fever, rash, hepatitis, lymphadenopathy, eosinophilia.

Metabolism and nutrition disorders common – anorexia, increased appetite.

Psychiatric disorders common – hostility, confusion, depression, anxiety, nervousness, thinking impaired, emotional lability; uncommon – mental status worsening; unknown – hallucinations.

Nervous system disorders very common – somnolence, dizziness, ataxia; common – convulsions, hyperkinesia, dysarthria, amnesia, tremor, insomnia, headache, disturbance in attention (e.g., paresthesias, hypesthesia), incoordination, nystagmus, increased, decreased or absent reflexes; uncommon – hypokinesia; rare – loss of consciousness; unknown – other movement disorders (e.g., choreoathetosis, dyskinesia and dystonia).

Eye disorders common – vision blurred (such as amblyopia, diplopia).

Ear and labyrinth disorders common – vertigo; unknown – tinnitus.

Cardiac disorders uncommon – palpitations.

Vascular disorders common – symptoms of vasodilation or arterial hypertension.

Respiratory, thoracic and mediastinal disorders common – dyspnea, bronchitis, pharyngitis, cough, rhinitis.

Gastrointestinal disorders common – constipation, diarrhea, dry mouth or pharynx, dyspepsia, flatulence, nausea, vomiting, abdominal pain, dental disease, gingivitis; unknown – pancreatitis.

Hepatobiliary disorders unknown – hepatitis, jaundice

Skin and subcutaneous tissue disorders common – facial edema, purpura (most often described as bruising occurring with physical trauma), skin rash, acne, pruritus; unknown – Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia, drug eruption, including eosinophilia and systemic symptoms.

Musculoskeletal and connective tissue disorders common – myalgia, arthralgia, back pain, muscle twitching; unknown – rhabdomyolysis, myoclonus.

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

Reproductive system and breast disorders common – impotence; unknown – breast enlargement, gynecomastia, sexual dysfunction (including libido changes, ejaculation disorder and anorgasmia).

General disorders and administration site conditions very common – fatigue, fever; common – peripheral edema, gait disturbance, asthenia, pain of various localization, malaise, flu-like syndrome; uncommon – generalized edema; unknown – withdrawal syndrome (the following adverse effects were most frequently noted: anxiety, insomnia, nausea, pain of various localization and increased sweating), chest pain. There is information on cases of sudden unexplained death that coincided in time with the intake of gabapentin. A causal relationship of these cases with gabapentin treatment has not been established.

Investigations common – decreased white blood cell count, increased body weight; uncommon – increased ALT, AST and plasma bilirubin concentration, hyperglycemia; rare – hypoglycemia (predominantly in patients with diabetes mellitus); unknown – hyponatremia, increased CPK activity.

Injury, poisoning and procedural complications: common – injuries, fractures, abrasions associated with falls.

There are reports of the development of acute pancreatitis during therapy with gabapentin. The causal relationship with gabapentin remains unclear.

There are reports of cases of myopathy with increased CPK activity in patients with end-stage renal failure undergoing hemodialysis.

Cases of respiratory tract infection, otitis media, bronchitis and convulsions were noted only in clinical studies.

In addition, cases of aggressive behavior and hyperkinesis in children were reported in clinical studies.

Contraindications

• Hypersensitivity to gabapentin or auxiliary components of the used dosage form;
• Epilepsy: use as monotherapy for partial seizures with and without secondary generalization in children under 12 years of age;
• Neuropathic pain: for the treatment of neuropathic pain in children and adolescents under 18 years of age;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption, included in the composition of the dosage form.

Use in Pregnancy and Lactation

General risk due to epilepsy and antiepileptic drugs

The risk of having children with congenital anomalies in mothers who are undergoing treatment with anticonvulsant drugs for epilepsy is increased 2-3 times. Cleft lip and palate, cardiovascular malformations and neural tube defects are most commonly observed. In this case, taking several anticonvulsant drugs 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 potential, as well as all women for whom pregnancy is possible, should consult a qualified specialist. If a woman is planning a pregnancy, the need to continue anticonvulsant therapy should be reassessed. At the same time, anticonvulsant drugs should not be discontinued abruptly, as this may lead to the resumption of seizures with severe consequences for the mother and child. In rare cases, developmental delay has been observed in children whose mothers have epilepsy. It is impossible to determine whether the developmental delay is related to genetic or social factors, the mother’s illness or anticonvulsant therapy.

Risk due to gabapentin

There are no data on the use of the drug in pregnant women. Experiments in animals have shown toxicity of the drug to the fetus. There are no data regarding the possible risk in humans. Therefore, Gabapentin should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the fetus.

In the cases reported, it is not possible to say with certainty whether or not the use of gabapentin during pregnancy is accompanied by an increased risk of malformations, firstly, due to the presence of epilepsy itself, and secondly, due to the use of other anticonvulsant drugs.

Breastfeeding

Gabapentin is excreted in breast milk, its effect on the breastfed infant is unknown, therefore during breastfeeding Gabapentin should be used only if the benefit to the mother clearly outweighs the risk to the infant.

Use in Renal Impairment

Patients with impaired renal function and patients undergoing hemodialysis require adjustment of the dosing regimen.

Pediatric Use

Use is contraindicated in children under 12 years of age.

Geriatric Use

Due to age-related decline in renal function, elderly patients may require dose adjustment. Somnolence, peripheral edema and asthenia may occur more frequently in elderly patients.

Special Precautions

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

Therefore, patients receiving these drugs should be closely monitored for the emergence or worsening of depression, the appearance of suicidal thoughts or behavior, as well as for any changes in behavior. If signs of suicidal thoughts or behavior appear, patients or their caregivers should consult a doctor.

If acute pancreatitis develops while taking gabapentin, the possibility of its discontinuation should be assessed.

Although a withdrawal syndrome accompanied by the development of seizures has not been noted with gabapentin treatment, abrupt discontinuation of anticonvulsant therapy in patients with epilepsy may provoke the development of status epilepticus.

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

Just as with other anticonvulsant drugs, attempts to discontinue all concomitant antiepileptic drugs in order to initiate gabapentin monotherapy in cases of treatment resistance in patients taking multiple anticonvulsants, mostly do not end successfully.

Gabapentin is considered ineffective in primary generalized seizures, for example, absences, and may even enhance such seizures in some patients. In this regard, Gabapentin should be used with caution in patients with mixed seizures, including absences.

Systematic studies of patients aged 65 years and older taking Gabapentin have not been conducted. In a double-blind study of gabapentin use for neuropathic pain in patients aged 65 years and older, a higher frequency of somnolence, peripheral edema and asthenia was observed compared to patients under 65 years of age. Apart from these findings, clinical examination of this group of patients showed that their adverse effect profile did not differ from the others.

The effect of long-term therapy (more than 36 weeks) with gabapentin on a child’s learning ability, intelligence and development has not been sufficiently studied. The ratio of possible risk and benefit should be assessed when prescribing long-term therapy.

The post-marketing surveillance database contains reports of cases of drug abuse and dependence. As with any drug affecting the CNS, physicians should carefully review patients’ history for drug abuse and monitor them for possible signs of gabapentin abuse (e.g., striving to obtain the drug unreasonably, development of tolerance to gabapentin therapy, unjustified increase in drug dose).

During the use of antiepileptic drugs, including gabapentin, cases of severe life-threatening hypersensitivity reactions, such as drug rash with eosinophilia and systemic symptoms, have been reported. It is necessary to remember that early signs of a hypersensitivity reaction, such as fever, lymphadenopathy, may develop even in the absence of a skin rash. If such symptoms appear, the patient should be examined immediately. If no other causes are found, except for the use of gabapentin, then its use should be discontinued.

The use of gabapentin may lead to the development of anaphylaxis. The following symptoms and signs were noted in cases of anaphylaxis during gabapentin use – difficulty breathing, swelling of the lips, larynx, and tongue; a pronounced decrease in blood pressure requiring urgent medical intervention was also observed. Patients should be warned that if signs or symptoms of anaphylaxis develop, they should discontinue the drug and seek medical help.

When gabapentin was used concomitantly with other anticonvulsants, false-positive results for protein in urine were reported using Ames N-Multistix SG^® test strips. For determining protein in urine, it is recommended to use the more specific sulfosalicylic acid precipitation method.

During treatment with gabapentin, cases of dizziness and drowsiness have been observed, which may increase the likelihood of accidental injury (from falls). Post-marketing reports have also included cases of confusion, loss of consciousness, and impaired mental activity. Therefore, patients should be advised to exercise caution until they are aware of the potential effects of gabapentin.

When used concomitantly with opioid analgesics, an increase in gabapentin plasma concentration may be observed. In this regard, the patient requires careful monitoring for the development of signs of CNS depression, such as drowsiness, sedation, and respiratory depression. The doses of gabapentin or opioid analgesics should be reduced.

Gabapentin is recommended to be taken approximately 2 hours after taking an antacid.

Effect on the Ability to Drive Vehicles and Operate Machinery

While taking the drug, patients are not recommended to drive vehicles or use potentially dangerous machinery until the absence of a negative impact of the drug on performing these functions is confirmed.

Gabapentin affects the CNS and can cause dizziness, drowsiness, confusion, loss of consciousness, or other CNS symptoms. Even when mild or moderate, these adverse effects can be dangerous for patients driving vehicles or operating other machinery. This likelihood is particularly high at the start of treatment or after an increase in the gabapentin dose.

Drug Interactions

There are reports of spontaneous cases, as well as information from literature sources, about possible respiratory depression and/or sedation symptoms associated with the use of gabapentin and opioid analgesics. In some of these cases, the authors associated these symptoms with the concomitant use of gabapentin and opioids, especially in elderly patients.

When 600 mg of gabapentin was administered 2 hours after taking 60 mg of morphine in extended-release capsules, an increase in the mean AUC of gabapentin by 44% was observed compared to gabapentin monotherapy, which was associated with an increase in the pain threshold (cold pressor test). The clinical significance of this change has not been established; the pharmacokinetic characteristics of morphine were unchanged. The side effects of morphine when taken concomitantly with gabapentin did not differ from those when morphine was taken with placebo. The extent of interaction of these drugs at other doses is unknown.

No interactions were observed between gabapentin and phenobarbital, phenytoin, valproic acid, and carbamazepine. The steady-state pharmacokinetics of gabapentin are the same in healthy individuals and patients receiving other anticonvulsant drugs.

Concomitant use of gabapentin with oral contraceptives containing norethisterone and/or ethinyl estradiol is not accompanied by changes in the pharmacokinetics of either component.

Concomitant use of gabapentin with antacids containing aluminum and magnesium is accompanied by a decrease in the bioavailability of gabapentin by approximately 24%.

Probenecid does not affect the renal excretion of gabapentin.

A small decrease (14%) in the renal excretion of gabapentin during concomitant use of cimetidine is probably not clinically significant.

During concomitant use of naproxen (250 mg) and gabapentin (125 mg), an increase in the absorption of gabapentin from 12% to 15% was noted. Gabapentin does not affect the pharmacokinetic parameters of naproxen. The indicated drug doses are lower than the minimum therapeutic doses. Concomitant use of these drugs at high doses has not been studied.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.