Active ingredients: Nimodipine
NIMOTOP 30 mg coated tablets
NIMOTOP 30 mg / 0.75 mL oral drops, solution
Nimotop package inserts are available for pack sizes: - NIMOTOP 30 mg coated tablets, NIMOTOP 30 mg / 0.75 mL oral drops, solution
- NIMOTOP 10 mg / 50 mL solution for intravenous infusion
Indications Why is Nimotop used? What is it for?
Pharmacotherapeutic group
Selective calcium channel blocker; dihydropyridine derivative
Therapeutic indications
Prevention and therapy of ischemic neurological deficits related to cerebral vasospasm.
Contraindications When Nimotop should not be used
Nimotop must not be administered during pregnancy or lactation and in cases of hypersensitivity to the active substance or to any of the excipients.
Nimotop should not be administered concomitantly with rifampicin, as concomitant administration of rifampicin may significantly reduce the efficacy of nimodipine (see section "Interactions").
Severely impaired liver function, and particularly liver cirrhosis, may cause an increase in the bioavailability of nimodipine, due to a decrease in the first pass effect and metabolic clearance. For this reason, Nimotop should not be administered to patients with hepatic function. severely impaired (e.g. cirrhosis of the liver).
Concomitant therapy with oral nimodipine and antiepileptic drugs, such as phenobarbital, phenytoin or carbamazepine, is contraindicated, as concomitant use of these drugs may significantly reduce the efficacy of nimodipine (see "Interactions").
Precautions for use What you need to know before taking Nimotop
In very elderly patients with multiple conditions, in severely impaired renal function (glomerular filtration <20 ml / min) and in patients with severely impaired cardiovascular function, the need for treatment with Nimotop should be considered with caution and the patient should be regularly checked.
Although there is no evidence that treatment with Nimotop is associated with an increase in intracranial pressure, careful monitoring is recommended in these cases or in conditions characterized by a noticeable increase in the water content of the brain tissue (generalized brain edema).
Nimotop should also be used with caution in hypotensive patients (systolic blood pressure <100 mmHg).
In patients with unstable angina or in the first 4 weeks after an acute myocardial infarction, the physician should evaluate the potential risk (reduced coronary perfusion and myocardial ischaemia) in relation to the expected benefit (improved cerebral perfusion).
Interactions Which drugs or foods can modify the effect of Nimotop
Inform your doctor (or pharmacist) if you have recently taken any other medicines, those without a prescription.
Effects of other drugs on nimodipine
Nimodipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to inhibit or induce this enzyme system may therefore modify the first pass effect (after oral administration) or the clearance of nimodipine (see "Dose, method and time of administration").
The extent and duration of this interaction should be taken into consideration when nimodipine is administered concomitantly with the following drugs:
Rifampicin
Experience with other calcium channel blockers suggests that rifampicin accelerates the metabolism of nimodipine through an enzyme induction process.
Therefore, the efficacy of nimodipine could be significantly reduced when administered with rifampicin.
The use of nimodipine with rifampicin is therefore contraindicated (see "Contraindications").
Antiepileptic drugs inducing the cytochrome P450 3A4 system, such as phenobarbital, phenytoin or carbamazepine
Previous chronic therapy with the antiepileptic drugs phenobarbital, phenytoin or carbamazepine markedly reduces the bioavailability of orally administered nimodipine. Therefore, concomitant therapy with these drugs and oral nimodipine is contraindicated (see "Contraindications").
Inhibitors of the cytochrome P450 3A4 system
When co-administered with the following inhibitors of the cytochrome P450 3A4 system, blood pressure should be monitored and, if necessary, a reduction of the nimodipine dose should be considered (see "Dose, method and time of administration") .
Macrolide antibiotics (e.g. erythromycin)
No interaction studies have been performed between macrolide antibiotics and nimodipine. Some macrolide antibiotics are known inhibitors of the cytochrome P450 3A4 system and the possibility of an interaction at this level cannot be ruled out. Therefore macrolide antibiotics should not be used in combination with nimodipine (see "Special warnings").
Although structurally related to the macrolide class of antibiotics, azithromycin is not an inhibitor of the CYP 3A4 cytochrome system.
HIV protease inhibitors (e.g. ritonavir)
No full-fledged studies have been conducted to investigate the potential interaction between nimodipine and anti-HIV protease inhibitors. Certain drugs of this class have been reported to be potent inhibitors of the cytochrome P450 3A4 system. For this reason, the possibility of a marked and clinically relevant increase in plasma concentration of nimodipine when administered concomitantly with one of these drugs, cannot be excluded (see "Special warnings").
Azole antifungals (e.g. ketoconazole)
No full-fledged studies have been conducted to investigate the potential interaction between nimodipine and ketoconazole. Azole antifungals are known to inhibit the cytochrome P450 3A4 system, and various interactions have been reported for other dihydropyridine calcium channel blockers. Therefore, when co-administered with oral nimodipine, a substantial increase in systemic bioavailability cannot be excluded. nimodipine, due to a decrease in first pass metabolism (see "Special warnings").
Nefazodone
No full-fledged studies have been conducted to investigate the potential interaction between nimodipine and nefazodone. This antidepressant drug is known to be a potent inhibitor of the cytochrome P450 3A4 system. Therefore, if nefazodone is co-administered with nimodipine, a substantial increase in the plasma concentration of nimodipine cannot be excluded (see "Special warnings"
Fluoxetine
Co-administration of nimodipine with the antidepressant fluoxetine at steady state resulted in an approximately 50% increase in plasma levels of nimodipine. The concentration of fluoxetine was markedly decreased, while the concentration of its active metabolite norfluoxetine was not. affected (see "Special warnings").
Quinupristin / dalfopristin
Based on experience with the calcium channel blocker nifedipine, concomitant administration of nimodipine and quinupristin / dalfopristin may lead to increased plasma concentrations of nimodipine (see "Special warnings").
Cimetidine
Co-administration of nimodipine and cimetidine (an H2-antagonist) may lead to an increase in the plasma concentration of nimodipine (see "Special warnings").
Valproic Acid
Co-administration of nimodipine and valproic acid (an anticonvulsant) may lead to an increase in the plasma concentration of nimodipine (see "Special warnings").
Further interactions
Nortriptyline
The concomitant intake of nimodipine and nortriptyline at steady state led to a modest decrease in the concentration of nimodipine without affecting the plasma levels of nortriptyline.
Effects of nimodipine on other drugs
Antihypertensive drugs
Nimodipine may increase the hypotensive effect of concomitantly administered antihypertensive drugs, such as, for example:
- diuretics
- β-blockers
- ACE inhibitors
- A1 antagonists
- other calcium channel blockers
- α-blockers
- PDE5 inhibitors
- α-methyldopa
If such an association is unavoidable, particularly careful patient monitoring is required.
Zidovudine
In a monkey study, simultaneous intravenous administration of the anti-HIV drug zidovudine and bolus nimodipine induced a significant increase in the AUC of zidovudine, with a significant reduction in its volume of distribution and clearance.
Food interactions
Grapefruit juice
Grapefruit juice inhibits the cytochrome P450 3A4 system.
The simultaneous intake of grapefruit juice and diiprodipyridine calcium channel blockers increases the plasma concentration and duration of action of the latter, due to a decrease in its first pass metabolism or its clearance. As a consequence of this, the antihypertensive effect of nimodipine may be enhanced. This phenomenon may last for at least 4 days after the last ingestion of grapefruit juice. Ingestion of grapefruit or grapefruit juice should therefore be avoided during treatment with nimodipine (see "Dose, method and time of administration").
Cases in which an interaction has not been highlighted
Haloperidol
Co-administration of steady-state nimodipine to patients on long-term treatment with haloperidol revealed no potential for reciprocal interactions.
Co-administration of oral nimodipine and diazepam, digoxin, glibenclamide, indomethacin, ranitidine and warfarin did not reveal any potential reciprocal interactions.
Warnings It is important to know that:
Nimodipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to inhibit or induce this enzyme system may therefore modify the first pass effect or clearance of nimodipine (see "Interactions" and "Dose, method and time of administration").
Drugs known to inhibit the cytochrome P450 3A4 system and therefore may cause an increase in the plasma concentration of nimodipine are, for example:
- macrolide antibiotics (e.g. erythromycin)
- HIV protease inhibitors (e.g. ritonavir)
- azole antifungals (e.g. ketoconazole)
- the antidepressants nefazodone and fluoxetine
- quinupristin / dalfopristin
- cimetidine
- valproic acid.
When co-administered with these drugs, blood pressure should be monitored and, if necessary, a reduction of the nimodipine dose should be considered.
Additionally, for nimodipine oral solution:
Nimotop 30 mg / 0.75 ml oral drops, solution contains 48.06 vol% ethanol (alcohol), which is equivalent to 4.3 g per daily dose (9 ml). This can be harmful to people suffering from alcoholism or suffering from impaired alcohol metabolism, and should also be taken into consideration in pregnant or lactating women, children and high-risk groups, such as patients with liver disease or epilepsy. The amount of alcohol in this medicine may alter the effect of other medicines (see "Interactions"), as well as the ability to drive and use machines (see "Ability to drive and use machinery "). This medicine also contains hydrogenated polyhydric castor oil, which can cause stomach upset and diarrhea.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
There are no adequate controlled studies in pregnant women. If it is considered necessary to administer Nimotop during pregnancy, the expected benefits and potential risks should be carefully considered in relation to the severity of the clinical picture.
Feeding time
It has been shown that nimodipine and its metabolites are excreted in breast milk in a concentration of the same order of magnitude as that present in maternal plasma. Mothers are advised not to breastfeed while taking the drug.
Fertility
In individual cases of in-vitro fertilization, calcium channel blockers have been associated with reversible biochemical changes in the sperm head, possibly resulting in impaired sperm function. The relevance of this finding is unknown in short-term treatment
Effects on ability to drive and use machines
In principle, the ability to drive and use machines may be impaired due to the possible occurrence of dizziness.
Additionally for Nimotop oral drops, solution:
The amount of alcohol in this medicine may affect your ability to drive and use machines (see "Special warnings").
For those who play sports:
The use of medicines containing ethyl alcohol can determine positive doping tests in relation to the alcohol concentration limits indicated by some sports federations.
Dosage and method of use How to use Nimotop: Dosage
Dosage
Unless otherwise prescribed, the average daily dose is 30 mg x 3 times (1 tablet x 3 times or 0.75 ml of solution x 3 times).
In the case of Nimotop 30 mg / 0.75 ml oral drops, solution, 0.75 ml of solution are equal to 30 mg of nimodipine and correspond to the dropper filled up to the mark.
In patients who develop side effects, the dose should be reduced as needed or treatment discontinued.
In case of concomitant administration with inhibitors or inducers of the CYP 3A4 system, dose modulation may be necessary (see "Interactions").
In the prophylaxis and treatment of ischemic neurological deficits resulting from cerebral vasospasm induced by subarachnoid haemorrhage, after parenteral therapy, it is recommended to continue the administration of nimodipine orally for about 7 days (60 mg - 2 tablets of 30 mg or 1, 5 mL of solution corresponding to 2 droppers filled up to the mark - 6 times a day, at 4 hour intervals
Special populations
The safety and efficacy of Nimotop in patients under the age of 18 has not been established.
Patients with impaired liver function
Severely impaired liver function, and particularly liver cirrhosis, may cause an increase in the bioavailability of nimodipine, due to a decrease in the first pass effect and metabolic clearance. Pharmacological effects and undesirable effects, such as lowering of blood pressure arterial, may be more pronounced in these patients.
In these cases the dose should be reduced or, if necessary, treatment discontinuation considered.
Patients with impaired renal function
In patients with severely impaired renal function (glomerular filtration <20 ml / min), the need for treatment with Nimotop should be considered with caution and the patient regularly monitored.
In case of severe renal impairment, any undesirable effects, such as lowering of blood pressure, may be more pronounced; in these cases, if necessary, the dose should be reduced or treatment discontinued.
Method of administration
Nimotop should be taken between meals, taking the tablets with a little liquid and the drops diluted in a little water.
Do not take with grapefruit juice (see "Interactions").
Do not immerse the dropper in water and do not rinse it.
After putting the drops in the water put the dropper back in the bottle.
The interval between single administrations should not be less than 4 hours.
Overdose What to do if you have taken too much Nimotop
Symptoms of intoxication:
Acute overdose symptoms that need to be considered are: marked hypotension, tachycardia or bradycardia; gastrointestinal disturbances and nausea.
Treatment of intoxication
In the event of acute overdose, administration of nimodipine should be discontinued immediately. Emergency measures must be aimed at eliminating the symptoms.
Gastric lavage with the addition of activated charcoal can be considered as an emergency measure. In case of severe hypotension, dopamine or noradrenaline can be administered intravenously. Since no specific antidote is known, treatment of adverse events should be aimed at eliminating the main symptoms.
In case of accidental ingestion / intake of an excessive dose of Nimotop, notify your doctor immediately or go to the nearest hospital.
IF IN ANY DOUBT ABOUT USING NIMOTOP, CONTACT YOUR DOCTOR OR PHARMACIST.
Side Effects What are the side effects of Nimotop
Like all medicines, Nimotop can cause side effects, although not everybody gets them.
Table 1 lists the adverse drug reactions reported with nimodipine in clinical studies with nimodipine under the indication "Prevention and therapy of ischemic neurological deficits related to cerebral vasospasm induced by subarachnoid haemorrhage", sorted by frequency categories according to CIOMS III ( in the placebo-controlled studies 703 patients were treated with nimodipine and 692 with placebo; in the uncontrolled studies 2,496 patients were treated with nimodipine; status 31 August 2005).
Within each frequency class, undesirable effects are reported in descending order of severity.
The frequencies are defined as follows:
very common (≥ 1/10)
common (≥ 1/100 to <1/10),
uncommon (≥ 1 / 1,000 to <1/100),
rare (≥ 1 / 10,000 to <1 / 1,000),
very rare (<1 / 10,000).
Table 1: Adverse Drug Reactions Reported in Patients in Clinical Trials for the "Prevention and Treatment of Ischemic Neurological Deficits Related to Cerebral Vasospasm" indication.
Table 2 lists the adverse drug reactions reported with nimodipine in clinical trials with nimodipine under the indication "Treatment of ischemic neurological deficits (impaired brain function in the elderly, IBFO)" and reported in "post-marketing experience", sorted by frequency category according to CIOMS III (in the placebo-controlled studies 1,594 patients were treated with nimodipine and 1,558 with placebo; in the uncontrolled studies 8,049 patients were treated with nimodipine; status 20 October 2005).
Within each frequency class, undesirable effects are reported in descending order of severity.
The frequencies are defined as follows:
common (≥ 1/100 to <1/10),
uncommon (≥ 1 / 1,000 to <1/100),
rare (≥ 1 / 10,000 to <1 / 1,000),
very rare (<1 / 10,000).
Table 2: Adverse Drug Reactions Reported in Patients in Clinical Trials "Treatment of Ischemic Neurological Deficits (Impaired Brain Function in the Elderly, IBFO)"
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package.
The expiry date refers to the last day of the month.
Special precautions for storage
Tablets: none
Oral drops, solution: protect from light / do not refrigerate
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Keep this medicine out of the reach and sight of children.
Composition
NIMOTOP 30 mg coated tablets
one coated tablet contains:
active ingredient: nimodipine 30 mg.
excipients: microgranular cellulose, povidone, crospovidone, magnesium stearate, corn starch, hypromellose, macrogol 4000, titanium dioxide, yellow iron oxide.
NIMOTOP 30 mg / 0.75 mL oral drops, solution
0.75 mL of Nimotop oral drops contain:
active ingredient: nimodipine 30 mg.
excipients: hydrogenated polyhydric castor oil, ethyl alcohol.
Pharmaceutical form and content
36 coated tablets of 30 mg
1 bottle of 25 mL of oral drops, with dropper.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
NIMOTOP
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
NIMOTOP 30 mg coated tablets one coated tablet contains:
active ingredient: nimodipine 30 mg.
NIMOTOP 30 mg / 0.75 mL oral drops, solution 0.75 mL of solution contain:
active ingredient: nimodipine 30 mg.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Coated tablet. Oral drops, solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Prevention and therapy of ischemic neurological deficits related to cerebral vasospasm.
04.2 Posology and method of administration
Special populations
The safety and efficacy of Nimotop in patients under the age of 18 has not been established.
Dosage
Unless otherwise prescribed, the recommended daily dose is 30 mg x 3 times (1 tablet or 0.75 mL of solution x 3 times). 0.75 mL of solution is equal to 30 mg of nimodipine and corresponds to the dropper filled up to the mark.
In patients who develop adverse reactions, the dose should be reduced as needed or treatment discontinued.
In case of concomitant administration with inhibitors or inducers of the CYP 3A4 system, dose modulation may be required (see section 4.5).
In the prophylaxis and treatment of ischemic neurological deficits resulting from cerebral vasospasm induced by subarachnoid haemorrhage, after parenteral therapy, it is recommended to continue the administration of nimodipine orally for about 7 days (60 mg - 2 tablets of 30 mg or 1, 5 ml of solution, corresponding to 2 droppers filled up to the mark - 6 times a day, at 4 hour intervals).
Patients with impaired liver function
Severely impaired liver function, and particularly liver cirrhosis, may cause an increase in the bioavailability of nimodipine, due to a decrease in the first pass effect and metabolic clearance. Pharmacological effects and undesirable effects, such as lowering of blood pressure , may be more pronounced in these patients.
In these cases the dose should be reduced or, if necessary, treatment discontinuation considered.
Patients with impaired renal function
In patients with severely impaired renal function (glomerular filtration
In case of severe renal impairment, any undesirable effects, such as lowering of blood pressure, may be more pronounced; in these cases, if necessary, the dose should be reduced or treatment discontinued.
Method of administration
Nimotop should be taken between meals, the tablets with a little liquid, the drops diluted in a little water.
Do not take with grapefruit juice (see section 4.5).
Do not immerse the dropper in the water and do not rinse it. After putting the drops into the water, return the dropper to the bottle.
The interval between single administrations should not be less than 4 hours.
04.3 Contraindications
Nimotop must not be administered during pregnancy or lactation and in case of hypersensitivity to the active substance or to any of the excipients.
Concomitant use of nimodipine with rifampicin is contraindicated as concomitant use of rifampicin may significantly reduce the efficacy of nimodipine (see section 4.5).
Concomitant therapy with oral nimodipine and antiepileptic drugs, such as phenobarbital, phenytoin or carbamazepine, is contraindicated as concomitant use of these drugs may significantly reduce the efficacy of nimodipine (see section 4.5).
Severely impaired liver function, and particularly liver cirrhosis, may cause an increase in the bioavailability of nimodipine, due to a decrease in the first pass effect and metabolic clearance. Pharmacological effects and undesirable effects, such as lowering of blood pressure , may be more pronounced in these patients.
In these cases the dose should be reduced or, if necessary, treatment discontinuation considered.
04.4 Special warnings and appropriate precautions for use
In very elderly patients with multiple pathologies, in case of severely impaired renal function (glomerular filtration
Although there is no evidence that treatment with Nimotop is associated with an increase in intracranial pressure, careful monitoring is recommended in these cases or in conditions characterized by an increase in the water content of the brain tissue (generalized brain edema).
Nimotop should also be used with caution in hypotensive patients (systolic blood pressure
In patients with unstable angina or in the first 4 weeks after an acute myocardial infarction, the physician should evaluate the potential risk (reduced coronary perfusion and myocardial ischaemia) in relation to the expected benefit (improved cerebral perfusion).
Nimodipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to inhibit or induce this enzyme system may therefore modify the first pass effect or clearance of nimodipine (see sections 4.2 and 4.5).
Drugs known to inhibit the cytochrome P450 3A4 system, and therefore may cause an increase in the plasma concentration of nimodipine, are, for example:
- macrolide antibiotics (e.g. erythromycin)
- anti-HIV protease inhibitors (e.g. ritonavir)
- azole antifungals (e.g. ketoconazole)
- the antidepressants nefazodone and fluoxetine
- quinupristin / dalfopristin
- cimetidine
- valproic acid.
Upon concomitant administration of these drugs, blood pressure should be monitored and, if necessary, a reduction of the nimodipine dose should be considered.
In addition, for nimodipine oral solution: Nimotop 30 mg / 0.75 ml oral drops, solution contains 48.06 vol% ethanol (alcohol), which is equivalent to up to 4.3 g per daily dose (9 ml). This can be harmful to people suffering from alcoholism or suffering from impaired alcohol metabolism, and should also be taken into consideration in pregnant or lactating women, children and high-risk groups such as patients with liver disease or epilepsy. The amount of alcohol in this medicine may alter the effect of other drugs (see section 4.5), as well as the ability to drive and use machines (see section 4.7). This medicine also contains hydrogenated polyhydric castor oil, which can cause stomach upset and diarrhea.
04.5 Interactions with other medicinal products and other forms of interaction
Effects of other drugs on nimodipine
Nimodipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to inhibit or induce this enzyme system may therefore modify the first pass effect or clearance of nimodipine (see section 4.2."Patients with impaired liver function").
The extent and duration of this interaction should be taken into consideration when nimodipine is administered concomitantly with the following drugs:
Rifampicin
Experience with other calcium channel blockers suggests that rifampicin accelerates the metabolism of nimodipine through an enzyme induction process. Therefore, the efficacy of nimodipine could be significantly reduced when administered with rifampicin.
The use of nimodipine with rifampicin is therefore contraindicated (see section 4.3).
Antiepileptic drugs inducing the cytochrome P450 3A4 system, such as phenobarbital, phenytoin or carbamazepine.
Previous chronic therapy with the antiepileptic drugs phenobarbital, phenytoin or carbamazepine markedly reduces the bioavailability of orally administered nimodipine. Therefore, concomitant therapy with these drugs and oral nimodipine is contraindicated (see section 4.3).
Inhibitors of the cytochrome P450 3A4 system
When co-administered with the following inhibitors of the cytochrome P450 3A4 system, blood pressure should be monitored and, if necessary, a dose reduction of nimodipine should be considered (see section 4.2).
Macrolide antibiotics (e.g. erythromycin)
No interaction studies have been conducted between macrolide antiobiotics and nimodipine. Some macrolide antibiotics are known inhibitors of the cytochrome P450 3A4 system and the possibility of an interaction at this level cannot be ruled out. Therefore macrolide antibiotics should not be used in combination with nimodipine (see section 4.4).
Although structurally related to the macrolide class of antibiotics, azithromycin is not an inhibitor of the CYP 3A4 cytochrome system.
HIV protease inhibitors (e.g. ritonavir)
No full-fledged studies have been conducted to investigate the potential interaction between nimodipine and anti-HIV protease inhibitors. Some drugs of this class have been reported to be potent inhibitors of the cytochrome P450 3A4 system. For this reason, the possibility of a marked and clinically relevant increase in the plasma concentration of nimodipine when administered concomitantly with one of these drugs cannot be excluded (see section 4.4).
Azole antifungals (e.g. ketoconazole)
No full-fledged studies have been conducted to investigate the potential interaction between nimodipine and ketoconazole. Azole antifungals are known to inhibit the cytochrome P450 3A4 system, and various interactions have been reported for other dihydropyridine calcium channel blockers. Therefore, when co-administered with oral nimodipine, a substantial increase in the systemic bioavailability of nimodipine due to a decrease in first pass metabolism cannot be excluded (see section 4.4).
Nefazodone
No full-fledged studies have been conducted to investigate the potential interaction between nimodipine and nefazodone. This antidepressant drug is known to be a potent inhibitor of the cytochrome P450 3A4 system. Therefore, when nefazodone is co-administered with nimodipine, a substantial increase in the plasma concentration of nimodipine cannot be excluded (see section 4.4).
Fluoxetine
Co-administration of nimodipine with the antidepressant fluoxetine at steady state resulted in an approximately 50% increase in plasma levels of nimodipine. The concentration of fluoxetine was markedly decreased, while the concentration of its active metabolite norfluoxetine was not. affected (see section 4.4).
Quinupristin / dalfopristin
Based on experience with the calcium channel blocker nifedipine, concomitant administration of nimodipine and quinupristin / dalfopristin may lead to increased plasma concentrations of nimodipine (see section 4.4).
Cimetidine
Co-administration of nimodipine and cimetidine (an H2 antagonist) may lead to an increase in the plasma concentration of nimodipine (see section 4.4).
Valproic acid
Co-administration of nimodipine and valproic acid (an anticonvulsant) may lead to an increase in the plasma concentration of nimodipine (see section 4.4).
Further interactions
Nortriptyline
The concomitant intake of nimodipine and nortriptyline at steady state led to a modest decrease in the concentration of nimodipine without affecting the plasma levels of nortriptyline.
Effects of nimodipine on other drugs
Antihypertensive drugs
Nimodipine may increase the hypotensive effect of concomitantly administered antihypertensive drugs, such as, for example:
- diuretics
- beta blockers
- ACE inhibitors - A1 antagonists
- other calcium channel blockers
- α-blockers
- PDE5 inhibitors
- α-methyldopa
If such an association is unavoidable, particularly careful patient monitoring is required.
Zidovudine
In a monkey study, simultaneous intravenous administration of the anti-HIV drug zidovudine and bolus nimodipine induced a significant increase in the AUC of zidovudine, with a significant reduction in its volume of distribution and clearance.
Food interactions
Grapefruit juice
Grapefruit juice inhibits the cytochrome P450 3A4 system. The simultaneous intake of grapefruit juice and diiprodipyridine calcium channel blockers increases the plasma concentration and duration of action of the latter, due to a decrease in its first pass metabolism or its clearance. As a consequence of this, the antihypertensive effect of nimodipine may be enhanced. This phenomenon may last for at least 4 days after the last ingestion of grapefruit juice. Ingestion of grapefruit or grapefruit juice should therefore be avoided during treatment with nimodipine (see section 4.2).
Cases in which an interaction has not been highlighted
Haloperidol
Co-administration of steady-state nimodipine to patients on long-term treatment with haloperidol revealed no potential for reciprocal interactions.
Co-administration of oral nimodipine and diazepam, digoxin, glibenclamide, indomethacin, ranitidine and warfarin did not reveal any potential reciprocal interactions.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate controlled studies in pregnant women.
If it is considered necessary to administer Nimotop during pregnancy, the expected benefits and potential risks should be carefully considered in relation to the severity of the clinical picture.
Feeding time
Nimodipine and its metabolites have been shown to be excreted in human milk in a concentration of the same order of magnitude as that present in maternal plasma. Mothers are advised not to breastfeed while taking the medicine.
Fertility
In individual cases of in-vitro fertilization, calcium channel blockers have been associated with reversible biochemical changes in the sperm head, possibly resulting in impaired sperm function. The relevance of this finding is unknown in short-term treatment.
04.7 Effects on ability to drive and use machines
In principle, the ability to drive and use machines may be impaired in connection with the possible occurrence of dizziness.
Additionally for Nimotop oral drops, solution:
The amount of alcohol in this medicinal product may affect the ability to drive and use machines (see section 4.4).
04.8 Undesirable effects
Table 1 lists the adverse drug reactions reported with nimodipine in clinical studies with nimodipine under the indication "Prevention and therapy of ischemic neurological deficits related to cerebral vasospasm induced by subarachnoid haemorrhage", sorted by frequency categories according to CIOMS III ( in the placebo-controlled studies 703 patients were treated with nimodipine and 692 with placebo; in the uncontrolled studies 2,496 patients were treated with nimodipine; status 31 August 2005).
Within each frequency class, undesirable effects are reported in descending order of severity.
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100,
Table 1: Adverse Drug Reactions Reported in Patients in Clinical Trials for the "Prevention and Treatment of Ischemic Neurological Deficits Related to Cerebral Vasospasm" indication.
Table 2 lists the adverse drug reactions reported with nimodipine in clinical studies with nimodipine on the "indication"Treatment of ischemic neurological deficits (impaired brain function in the "elderly, IBFO)" and reported in post-marketing experience, sorted by frequency categories according to CIOMS III (in the placebo-controlled studies 1,594 patients were treated with nimodipine and 1,558 with placebo; in uncontrolled studies 8,049 patients were treated with nimodipine; status 20 October 2005).
Within each frequency class, undesirable effects are reported in descending order of severity.
Frequencies are defined as follows: common (≥ 1/100,
Table 2: Adverse Drug Reactions Reported in Patients in Clinical Trials Indication "Treatment of Ischemic Neurological Deficits (Impaired Brain Function in the Elderly, IBFO)".
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Symptoms of intoxication:
Acute overdose symptoms that need to be considered are: marked hypotension, tachycardia or bradycardia; gastrointestinal disturbances and nausea.
Treatment of intoxication
In the event of acute overdose, administration of nimodipine should be discontinued immediately. Emergency measures must be aimed at eliminating the symptoms.
Gastric lavage with the addition of activated charcoal can be considered as an emergency measure. In case of severe hypotension, dopamine or noradrenaline can be administered intravenously. Since no specific antidote is known, treatment of adverse events should be aimed at eliminating the main symptoms.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "Street address
www.aifa.gov.it/responsabili
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective calcium channel blocker, dihydropyridine derivative.
ATC code: C08CA06.
Nimodipine is a calcium antagonist belonging to the 1,4 dihydropyridine class, which differs from other calcium antagonists due to its marked selectivity of action in the cerebral district.
Thanks to its high lipophilicity, nimodipine easily crosses the blood brain barrier. In animal studies, nimodipine has been shown to bind with high affinity and selectivity to L-type Ca ++ channels, thereby blocking the intracellular influx of calcium across the membrane.
Nimodipine protects neurons and stabilizes their functionality, promotes cerebral blood flow and increases resistance to ischemia through an action on neuronal and cerebrovascular receptors connected to calcium channels.
In pathological states associated with an increase in the intracytoplasmic influx of calcium into nerve cells, for example during cerebral ischemia, nimodipine is believed to improve the stability and functional capacity of these cellular elements.
The selective blockade of calcium channels in some brain areas, such as the hippocampus and cortex, may perhaps explain the positive effect of nimodipine on learning and memory deficits observed in several animal models.
The same molecular mechanism is probably at the basis of the vasodilatory effect in the brain and blood flow promotion of nimodipine observed in animals and humans.
Its therapeutic properties are related to the ability to inhibit the contraction of the smooth muscle cell induced by calcium ions.
With the use of nimodipine, vasoconstriction induced in vitro by various vasoactive substances (such as serotonin, prostaglandins, histamine) and vasoconstriction caused by the blood or its degradation products can be prevented or resolved. Nimodipine also exerts neuro- and psychopharmacological effects. Research carried out in patients suffering from acute cerebrovascular disorders, have shown that nimodipine dilates the cerebral vessels and increases the cerebral blood flow, which is usually more consistently increased in the injured and hypoperfused cerebral districts, than in the healthy areas. Other studies have shown that this does not lead to stealing phenomena. With the use of nimodipine a significant reduction in ischemic neurological deficits and mortality is obtained following vasospasm due to subarachnoid hemorrhage of aneurysmal origin.
The improvement is significant only in patients with subarachnoid hemorrhage cerebral vasospasm. Concentrations of nimodipine up to 12.5 ng / mL have been detected in the cerebrospinal fluid of patients treated for subarachnoid haemorrhage.
Nimodipine has been clinically shown to improve memory and concentration impairments in patients with impaired brain function.
Other typical symptoms are also favorably influenced, as demonstrated by the evaluation of the overall clinical impression, the evaluation of individual disorders, observation of behavior and psychometric tests.
05.2 "Pharmacokinetic properties
Absorption
The active substance nimodipine, administered orally, is absorbed practically completely.
The unchanged active substance and its first first pass metabolites are detected in the plasma as early as 10-15 minutes after taking the tablet.
Following multiple oral doses (3 x 30 mg / day), peak plasma concentrations (Cmax) in the elderly are 7.3-43.2 ng / mL and are reached after 0.6-1 , 6 h (tmax).
Single doses of 30 mg and 60 mg in young subjects achieve mean peak plasma concentrations of 16 8 ng / mL and 31 12 ng / mL, respectively.
The peak plasma concentration and the area under the concentration / time curve increase dose proportionally up to the maximum dose studied (90 mg).
Mean steady-state plasma concentrations of 17.6 - 26.6 ng / mL are achieved after i.v. continuous of 0.03 ng / kg / h. After i.v. bolus plasma concentrations of nimodipine decline in a biphasic manner, with half-lives of 5-10 minutes and approximately 60 minutes. The calculated volume of distribution (Vss in the two-compartment model) for i.v. results of 0.9 - 1.6 l / kg of body weight. Total systemic clearance is 0.6 - 1.9 l / h / kg.
Protein binding and distribution
Nimodipine is 97-99% bound to plasma proteins.
In the experimental animal treated with 14C-labeled nimodipine, the radioactivity crosses the placental barrier.
A similar distribution is likely also in women, although there is a lack of experimental evidence in this sense.
In rats, nimodipine and / or its metabolites appear in milk at a much higher concentration than in maternal plasma. In women, the unchanged drug appears in milk at concentrations of the same order of magnitude as in maternal plasma.
After oral and intravenous administration, nimodipine can be determined in the cerebrospinal fluid at concentrations equal to approximately 0.5% of those found in plasma.
These correspond approximately to the concentrations of free active substance in the plasma.
Metabolism, elimination and excretion
The metabolism of nimodipine occurs through the cytochrome P450 3A4 system, mainly through dehydrogenation of the dihydropyridine ring and oxidative deesterification of the ester, which represents, with the hydroxylation of ethyl groups 2 and 6 and glucuronidation, one of the further important steps metabolic.
The three primary metabolites appearing in plasma possess therapeutically insignificant or zero "residual activity".
The effects of induction and inhibition on liver enzymes are unknown. In humans, approximately 50% of the metabolites are excreted via the renal emunctory, and 30% in the bile.
The kinetics of elimination are linear. The half-life of nimodipine is between 1.1 and 1.7 hours. The terminal half-life of 5-10 hours is not relevant in determining the interval between doses.
Mean plasma concentration curves of nimodipine after oral administration of 30 mg in the tablet formulation, and after i.v. of 0.015 mg / kg for 1 h (n = 24 elderly volunteers).
Bioavailability
Following the relevant first pass metabolism (about 85-95%), the absolute bioavailability is 5-15%.
05.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity. In rats, doses of 30 mg / kg / day or higher, administered during pregnancy, inhibited fetal growth, resulting in a decrease in fetal weight. A dose of 100 mg / kg / day was fatal to the fetus. There was no evidence of teratogenicity. In rabbits, no embryotoxicity and teratogenicity were observed up to a dose of 10 mg / kg / day. In a peri-postnatal study in rats, mortality and retardation in physical development were observed at doses of 10 mg / kg / day or more. These results were not confirmed by subsequent studies.
Acute toxicity
Table 3
The difference between the LD50 values after oral and intravenous administration indicates how, after the administration of high doses of an oral suspension formulation, the absorption of the active ingredient is incomplete or delayed.
Symptoms of poisoning after oral administration were observed only in mice and rats and are represented by mild cyanosis, severe decreased motility and dyspnoea.
Following IV administration, these signs of poisoning associated with tonic-clonic seizures were observed in all species studied.
Subchronic Tolerability Studies
Studies conducted in dogs at the oral dose of 10 mg / kg resulted in decreased body weight, decreased hematocrit, hemoglobin and erythrocytes; increased heart rate and changes in blood pressure.
Chronic Tolerability Studies
Oral dosages up to approximately 90 mg / kg / day for two years were well tolerated by the mouse.
In a 1-year study in dogs, the systemic tolerability of nimodipine doses up to 6.25 mg / kg / day was investigated.
Doses up to 2.5 mg / kg were found to be harmless, while 6.25 mg / kg caused electrocardiographic changes due to disturbances in myocardial blood flow. However, no cardiac histopathological changes were found at this dosage.
Reproductive Toxicity Studies
Fertility studies in the rat
Dosages up to 30 mg / kg / day did not affect the fertility of male and female rats or that of subsequent generations.
Embryotoxicity studies
The administration of 10 mg / kg / day to the female rat during embryogenesis did not reveal any harmful effects while dosages of 30 mg / kg / day and more inhibited growth inducing a reduced fetal weight and, at 100 mg / kg / day, induced an increase in intrauterine embryonic deaths.
Embryotoxicity studies conducted in rabbits with oral dosages up to 10 mg / kg / day did not reveal any teratogenic or embryotoxic effects.
Perinatal and postnatal development in rats
In order to evaluate perinatal and postnatal development, studies were conducted in rats with doses up to 30 mg / kg / day.
In a study with 10 mg / kg / day and more, an increase in both perinatal and postnatal mortality and delayed physical development was observed. These results were not confirmed by subsequent studies.
Specific tolerability studies
Carcinogenesis
In a lifetime study in rats, treated for 2 years with dosages up to 1800 parts per million (approximately 90 mg / kg / day) in feed, no oncogenic potential was shown.
Similar results were obtained in mice treated for 21 months in a long-term study with 500 mg / kg / day orally.
Mutagenesis
Nimodipine has been validated in numerous mutagenicity studies which did not show significant mutagenic effects, gene induction and chromosomal mutations.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Coated tablets
microgranular cellulose, povidone, crospovidone, magnesium stearate, maize starch, hypromellose, macrogol 4000, titanium dioxide (E171), yellow iron oxide (E172)
Oral drops, solution
hydrogenated polyhydric castor oil, ethyl alcohol
06.2 Incompatibility
None known.
06.3 Period of validity
Coated tablets: 5 years.
Oral drops, solution: 5 years.
06.4 Special precautions for storage
Coated tablets: This medicine does not require any special storage conditions
Oral drops, solution: protect from light / do not refrigerate
06.5 Nature of the immediate packaging and contents of the package
Tablets:
36 tablets
PVC / aluminum or PVC-PVDC / aluminum or PP blisters
Oral drops, solution:
oral drops, solution: 25 mL bottle brown glass bottle with screw cap and glass dropper
06.6 Instructions for use and handling
No special instructions
07.0 MARKETING AUTHORIZATION HOLDER
Bayer S.p.A. - Viale Certosa, 130 - Milan
08.0 MARKETING AUTHORIZATION NUMBER
NIMOTOP 30 mg coated tablets
AIC 026403016
NIMOTOP 30 mg / 0.75 mL oral drops, solution
AIC 026403055
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First authorization: 27.07.87 (on the market since October 1987)
Authorization renewal: June 2010
