Nimodipine

Pharmacological properties

nifedipine has a pronounced selective effect in some parts of the brain. its therapeutic properties are associated with the ability to inhibit the contraction of smooth muscle cells caused by calcium ions.

Nimodipine protects neurons and stabilizes their function; it favorably affects the blood supply to the brain and increases tolerance to ischemia through interaction with neuron receptors and cerebrovascular receptors associated with calcium channels. Other studies have shown that this does not lead to the intracerebral phenomenon of robbery.

It has been clinically demonstrated that nimodipine reduces memory disorders and improves concentration in patients with impaired brain function.

Nimodipine has a positive effect on other typical symptoms, as evidenced by an assessment of general clinical indicators and individual disorders, as well as behavior monitoring and psychometric tests.

Pharmacokinetics Suction. The active substance nimodipine is almost completely absorbed by oral administration. C_max in blood plasma and AUC increases in proportion to the dose up to the highest studied dose (90 mg).

The calculated volume of distribution (Vss, two-chamber model) for iv administration is 0.9–1.6 l / kg body weight. The total (total) clearance is 0.6–1.9 l / h / kg.

Protein binding and distribution. Binding to blood proteins reaches 97–99%.

Metabolism and excretion. The withdrawal of nimodipine is carried out by metabolism through the cytochrome P450 3A4 system.

Bioavailability. Due to the intensive presystemic metabolism (about 85–95%), the absolute bioavailability is 5–15%.

Indications

Prevention and treatment of ischemic neurological disorders due to cerebrovascular spasm after subarachnoid hemorrhage due to rupture of aneurysm.

Treatment of elderly patients with functional brain disorders with severe symptoms.

Application

Treatment of patients with functional brain disorders. in the treatment of elderly patients with functional brain disorders, the recommended dose (unless another is prescribed by the doctor) is 1 tablet of Nemotan 3 times a day (30 mg of nimodipine 3 times a day).

In patients with significantly reduced renal function (glomerular filtration rate less than 20 ml / min), the need for treatment should be carefully considered and the patient examined systematically.

Prevention and treatment of ischemic neurological disorders due to cerebrovascular spasm after subarachnoid hemorrhage due to rupture of aneurysm. After a course of infusion therapy, Nemotan is prescribed orally at 60 mg (2 coated tablets) 6 times a day.

In case of adverse reactions, the dose should be reduced, and if necessary, stop using the drug.

Impaired liver function, especially with cirrhosis of the liver, can lead to an increase in the bioavailability of nimodipine due to a decrease in primary metabolism and a decrease in metabolic clearance. In this case, adverse reactions (for example, a decrease in blood pressure) may be more pronounced. In such cases, the dose must be reduced, and if necessary, discontinue use of the drug.

With the simultaneous use of the drug with inhibitors or inducers of CYP 3A4, dose adjustment may be required (see INTERACTIONS).

Swallow the tablets whole without chewing, with a small amount of liquid, regardless of food intake, at intervals of at least 4 hours. It is not recommended to use grapefruit juice simultaneously with the drug.

Children. The drug is not used in children.

Contraindications

The use of the drug is contraindicated in individuals with individual hypersensitivity to nimodipine or other components of the drug. the use of nimodipine in combination with rifampicin is contraindicated, since the simultaneous use of these drugs leads to a significant decrease in the effectiveness of nimodipine.

Antiepileptic drugs (phenobarbital, phenytoin, carbamazepine) significantly reduce the bioavailability of nimodipine, therefore, simultaneous use with these drugs is contraindicated.

Nimodipine should not be used for unstable angina and myocardial infarction and / or 1 month after their occurrence.

Severe impairment of liver function, especially with cirrhosis of the liver, can lead to increased bioavailability of nimodipine due to a decrease in primary metabolism and a decrease in metabolic clearance. Therefore, nimodipine should not be used for treatment of functional brain disorders in patients with severe hepatic impairment (e.g., cirrhosis).

Side effects

The following is a list of adverse reactions to the drug based on clinical studies of nimodipine for indications of “subarachnoid hemorrhage due to aneurysm”.

On the part of the blood system and lymphatic system: changes in blood counts, thrombocytopenia.

On the part of the immune system: acute hypersensitivity reactions, allergic reaction, rash.

From the nervous system: non-specific cerebrovascular symptoms, headache.

From the side of the heart: non-specific arrhythmias, tachycardia, bradycardia.

From the vascular system: non-specific cardiovascular symptoms, arterial hypotension, vasodilation.

From the digestive tract: gastrointestinal disorders, nausea, intestinal obstruction.

From the liver and biliary tract: mild and moderate reactions from the liver, transient increase in the activity of liver enzymes.

The following is a list of adverse reactions to the drug based on clinical studies of nimodipine according to the indications “treatment for functional brain disorders”.

On the part of the immune system: acute hypersensitivity reactions, allergic reaction, rash.

From the nervous system: non-specific cerebrovascular symptoms, headache, vertigo.

Nonspecific neurological symptoms: dizziness, hyperkinesia, tremor.

From the side of the heart: non-specific arrhythmias, palpitation, tachycardia.

Vascular disorders: non-specific cardiovascular symptoms, arterial hypotension, vasodilation, syncope, edema.

From the digestive tract: gastrointestinal disorders, constipation, diarrhea, flatulence.

special instructions

Treatment for functional brain disorders. in the treatment of elderly people, patients with severe renal impairment (glomerular filtration rate less than 20 ml / min) or severe pathology of the cardiovascular system, the need for treatment should be carefully considered and the patient should be examined systematically.

Prevention and treatment of ischemic neurological disorders due to cerebrovascular spasm after subarachnoid hemorrhage due to rupture of aneurysm. Although the use of nimodipine is not associated with an increase in intracranial pressure, in these cases or when the water content in the brain tissues is increased (generalized cerebral edema), careful monitoring of the patient is recommended.

Treatment for functional disorders of the brain or the prevention and treatment of ischemic neurological disorders due to spasm of cerebral vessels after subarachnoid hemorrhage due to rupture of the aneurysm.The use of nimodipine requires special care in case of arterial hypotension with a systolic blood pressure level below 100 mm Hg. Art.

Nimodipine is metabolized through the cytochrome P450 3A4 system. Therefore, drugs that affect this enzyme system can alter the primary metabolism or clearance of nimodipine.

Drugs that are inhibitors or inducers of the cytochrome P450 3A4 system can lead to an increase in plasma concentrations of nimodipine: macrolides (e.g. erythromycin), anti-HIV protease inhibitors (e.g. ritonavir), azole antifungal agents (e.g. ketoconazole), antidepressants nefazetinone and , quinupristine / dalphopristine, cimetidine, valproic acid.

With the combined use of these drugs, it is necessary to control blood pressure and, if necessary, consider reducing the dose of nimodipine.

Use during pregnancy or lactation

Pregnancy. Appropriate studies of the effect on pregnant women have not been conducted. If you need to use the drug during pregnancy, you should carefully weigh the benefits and potential risks of taking the drug, depending on the severity of the clinical picture.

Lactation. It was revealed that the concentration of nimodipine and its metabolites in human milk in the order of magnitude corresponds to that in maternal blood plasma. While taking the drug, mothers are not recommended to breastfeed babies.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. The ability to drive vehicles and mechanisms may be impaired due to the possible occurrence of dizziness.

Interactions

Nimodipine is metabolized through the cytochrome p450 3a4 system, localized both in the intestinal mucosa and in the liver. therefore, drugs that affect this enzyme system can alter the primary metabolism or clearance of nimodipine.

When using nimodipine simultaneously with the following drugs, the degree and duration of the interaction must be taken into account.

Based on experience with other calcium channel antagonists, rifampicin is known to enhance nimodipine metabolism due to enzyme induction. Thus, the simultaneous use of rifampicin and nimodipine leads to a significant decrease in the effectiveness of the latter. The use of Nemotan in combination with rifampicin is contraindicated.

Antiepileptic drugs (phenobarbital, phenytoin, carbamazepine) significantly reduce the bioavailability of nimodipine tablets, so the simultaneous use of Nemotan with these drugs is contraindicated.

With the combined use of the following inhibitors of the cytochrome P450 3A4 system, blood pressure should be monitored and, if necessary, consider dose adjustment of nimodipine.

No studies have been conducted on the interaction between nimodipine and macrolide antibiotics. It is known that some macrolide antibiotics (e.g. erythromycin) inhibit the cytochrome P450 3A4 system and the possibility of interaction between drugs at this stage cannot be ruled out. Despite this, macrolide antibiotics should not be used with nimodipine.

Azithromycin, which although structurally belongs to the class of macrolide antibiotics, is not inhibited by CYP 3A4.

No formal studies have been conducted to study the potential interaction between nimodipine and anti-HIV protease inhibitors (e.g. ritonavir). It was established that drugs of this class are potent inhibitors of the cytochrome P450 3A4 system. Taking this into account, it is impossible to exclude the possibility of a pronounced and clinically significant increase in the concentration of nimodipine in blood plasma with simultaneous use with protease inhibitors.

No formal studies have been conducted to study the potential interaction between nimodipine and ketoconazole. Azole antifungal agents are known to inhibit the cytochrome P450 3A4 system and various interactions have been reported for other calcium channel dihydropyridine antagonists. Therefore, with the simultaneous use of nimodipine tablets, a significant increase in the systemic bioavailability of nimodipine cannot be ruled out due to a decrease in primary metabolism.

No formal studies have been conducted to study the potential interaction between nimodipine and nefazodone. The antidepressant has been reported to be a potent inhibitor of cytochrome P450 3A4. Despite this, it is impossible to exclude the possibility of increasing the concentration of nimodipine in blood plasma with simultaneous use with nefazodone.

Long-term combined use of Nemotan and fluoxetine caused an increase in the concentration of nimodipine in blood plasma by almost 50%. The effect of fluoxetine was significantly reduced, but the effect of its active metabolite, norfluoxetine, was not.

Based on the experience with nifedipine, its simultaneous use with quinupristine / dalphopristine can lead to an increase in the concentration of nimodipine in blood plasma.

Concomitant use of the drug Nemotan and antagonist H₂receptors of cimetidine or valproic acid preparations can lead to increased plasma concentrations of nimodipine.

Long-term use of nimodipine with the antidepressant nortriptyline leads to a slight increase in the concentration of nimodipine in blood plasma; the concentration of nortriptyline remains unchanged.

Nimodipine can enhance the hypotensive effect of such antihypertensive drugs when used simultaneously: diuretics, β-adrenoreceptor blockers, ACE inhibitors, α₁-antagonists, other calcium antagonists, α-blocking substances, PDE-5 inhibitors, α-methyldopa.

However, if combinations of this type cannot be avoided, special monitoring of the patients condition is required.

A study on monkeys found that the simultaneous iv use of nimodipine and a drug for the treatment of patients with HIV zidovudine leads to a significant increase in AUC for zidovudine and a decrease in the volume of its distribution and clearance.

Grapefruit juice inhibits the cytochrome P450 3A4 system. The use of dihydropyridines, calcium channel antagonists, simultaneously with grapefruit juice leads to increased plasma concentrations and the prolonged action of nimodipine due to reduced primary metabolism or clearance. As a result, the hypotensive effect of the drug may increase. After consuming grapefruit juice, this effect can last at least 4 days, so the simultaneous use of grapefruit / grapefruit juice and nimodipine is not recommended.

Overdose

Symptoms: in acute overdose, severe arterial hypotension, tachycardia or bradycardia, nausea, gastrointestinal disorders are noted.

Treatment: in case of acute overdose, immediate withdrawal of the drug is recommended. When appointing emergency care, symptomatic therapy is indicated. As an emergency therapy, gastric lavage is recommended, followed by the use of activated carbon.

With a further decrease in blood pressure, iv norepinephrine or dopamine should be administered. Since the specific antidote is unknown, symptomatic therapy is also provided for other adverse reactions.

Storage conditions

At a temperature not exceeding 25 ° c in the original packaging.