Active ingredients: Nimodipine
ISKIDROP 30 mg / 0.75 ml oral drops, solution
Indications Why is Iskidrop used? What is it for?
ISKIDROP contains nimodipine and belongs to a group of medicines called selective calcium channel blockers (dihydropyridine derivatives), which work by inhibiting calcium ion channels.
ISKIDROP is indicated in adults to prevent and treat a decrease in the activity (deficit) of the nervous system caused by a lack of adequate blood supply to the brain (ischemia). Ischemia can occur as a result of sudden and prolonged contraction of the muscles of one or more arteries of the brain (cerebral vasospasm).
Talk to your doctor if you don't feel better or if you feel worse.
Contraindications When Iskidrop should not be used
Do not take ISKIDROP
- if you are allergic to nimodipine or any of the other ingredients of this medicine
- if you are pregnant or breast-feeding (see section "Pregnancy, breast-feeding and fertility")
- if you are taking rifampicin (an antibiotic, a medicine used to treat bacterial infections) at the same time. This drug could significantly reduce the efficacy of nimodipine (see section "Other medicines and ISKIDROP")
- if you have severe liver problems (eg liver cirrhosis, a chronic liver disease caused by inflammation), as the effectiveness of ISKIDROP may increase
- if you are taking concomitant medicines to treat epilepsy (a disease of the nervous system characterized by seizures and loss of consciousness). These medicines may significantly reduce the effectiveness of nimodipine (see section "Other medicines and ISKIDROP").
Precautions for use What you need to know before taking Iskidrop
Talk to your doctor or pharmacist before taking ISKIDROP:
- if you have generalized brain edema (rapid swelling of the brain tissue) or a noticeable increase in pressure inside the skull (intracranial pressure)
- if you have low blood pressure
- if you are very old and have multiple pathologies
- if you have severe heart problems or blood circulation problems
- if you have severe kidney problems
- if you are taking medicines that affect the enzyme system involved in the metabolism of nimodipine at the same time (see section "Other medicines and ISKIDROP"). Your doctor will evaluate the need to monitor your blood pressure and, if necessary, reduce the dose of nimodipine.
For those who carry out sports activities
ISKIDROP contains ethyl alcohol which can determine positivity in doping tests, in relation to the alcohol concentration limits indicated by some sports federations.
Children and adolescents
Do not give this medicine to children and adolescents between 0 and 18 years of age, as the safety and efficacy of this medicine have not yet been established.
Interactions Which drugs or foods can change the effect of Iskidrop
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
In particular, tell your doctor if you are taking any of the following medicines:
Drugs capable of accelerating the metabolism of nimodipine
- rifampicin (see section "Do not take ISKIDROP")
- phenobarbital, phenytoin, carbamazepine, drugs used to treat epilepsy (see section "Do not take ISKIDROP")
These drugs could cause a reduction in the effectiveness of ISKIDROP.
Drugs capable of reducing / inhibiting the metabolism of nimodipine
- macrolide antibiotics (e.g. erythromycin), medicines used to treat infections caused by a broad spectrum of bacteria. Although azithromycin belongs to the class of macrolide antibiotics, it can be used
- HIV protease inhibitors (eg ritonavir), medicines used to treat infections caused by the HIV virus (human immunodeficiency virus)
- azole antifungals (e.g. ketoconazole), drugs capable of fighting infections caused by fungi
- nefazodone and fluoxetine, medicines used to treat depression (antidepressants)
- quinupristin / dalfopristin, combination of two antibiotics used to treat bacterial infections
- cimetidine, an antihistamine medicine used to treat peptic ulcer (loss of blood from the inner walls of the stomach and duodenum)
- valproic acid, a drug used to treat seizures (uncontrolled and involuntary movements of the muscles) related to epilepsy.
These drugs may cause an increase in the plasma concentration of nimodipine (see section "Do not take ISKIDROP").
Nortriptyline
It is a drug used to treat depression. Co-administration with nimodipine causes a modest decrease in the concentration of the latter in the blood.
Antihypertensive drugs (drugs used to lower blood pressure)
Nimodipine may increase the blood pressure lowering effect of the following drugs:
- Diuretics
- Beta blockers
- ACE inhibitors
- A1 antagonists
- Other calcium channel blockers
- Alpha blockers
- PDE5 inhibitors (phosphodiesterase type 5)
- Alpha-methyldopa.
If the combination of nimodipine with the listed antihypertensive drugs is necessary, your doctor will closely monitor your condition.
Zidovudine
A drug used to treat HIV (human immunodeficiency virus) infections.
ISKIDROP with food and drink
Do not eat or take grapefruit or grapefruit juice while taking nimodipine, to avoid an increase in the antihypertensive effect of nimodipine. This phenomenon can occur for at least 4 days after the last ingestion of grapefruit juice.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Do not take ISKIDROP if you are pregnant or breastfeeding (see section "Do not take ISKIDROP").
Fertility
In some cases, taking this medicine can interfere with in vitro fertilization techniques.
Driving and using machines
Taking ISKIDROP may influence the ability to drive and use machines due to the possible occurrence of dizziness.
ISKIDROP contains macrogolglycerol hydroxystearate and ethyl alcohol
ISKIDROP contains macrogolglycerol hydroxystearate (derivative of castor oil) May cause diarrhea and stomach upset. ISKIDROP contains 60 vol% ethanol (alcohol) eg up to 681 mg per maximum single dose equivalent to 17 ml of beer and 7 ml of wine per serving.
It can be harmful to alcoholics. To be taken into consideration in pregnant or lactating women, in high-risk groups such as people with liver disease or epilepsy.
Dosage and method of use How to use Iskidrop: Dosage
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose is 30 mg to be taken 3 times a day (30 drops of solution 3 times).
The time interval between single administrations should not be less than 4 hours.
In the prevention and treatment of nervous system deficits caused by ischemia.
In the event of a deficit (decreased activity) of the nervous system caused by ischemia (lack of adequate blood supply to the brain) once administration into a vein has been completed, therapy should be continued with the administration of oral nimodipine for approximately 7 days (60 mg, corresponding to 60 drops of solution, six times a day, at 4 hour intervals).
Take ISKIDROP between meals, diluting the drops in a little water.
Do not take ISKIDROP with grapefruit juice (see section 2 "ISKIDROP with drink").
If you have severe kidney problems
If you have severe kidney problems your doctor will need to carefully consider whether treatment with ISKIDROP is necessary and will need to check you regularly.
If you have severe kidney and liver problems
If you have severe kidney and liver problems, your doctor may decide to reduce the dose of ISKIDROP or stop treatment, as some possible side effects, such as low blood pressure, may be more noticeable.
If you forget to take ISKIDROP
Do not take a double dose to make up for a forgotten dose.
If you stop taking ISKIDRP
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Iskidrop
In case of accidental ingestion / intake of an excessive dose of ISKIDROP, notify your doctor immediately or go to the nearest hospital where they will provide you with adequate treatment. The intoxication symptoms caused by taking too much ISKIDROP are:
- marked lowering of blood pressure (hypotension)
- rapid heartbeat (tachycardia)
- slow heartbeat (bradycardia)
- stomach and intestinal disorders
- nausea.
In these cases, stop taking the drug immediately.
Side Effects What are the side effects of Iskidrop
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience one or more side effects, please contact your doctor who will evaluate a dose reduction or discontinuation of treatment.
While taking ISKIDROP the following side effects may occur at the following frequency:
Common (may affect up to 1 in 10 people):
- lowering of blood pressure
- increase in the diameter of blood vessels (vasodilation)
Uncommon (may affect up to 1 in 100 people):
- reduction in the number of platelets in the blood (thrombocytopenia)
- allergic reaction, rash
- headache
- rapid heartbeat (tachycardia)
- nausea
- dizziness
- sense of dizziness
- hyperkinesis (nervous system disorder characterized by involuntary and uncoordinated movements)
- tremors
- palpitations (intense perception of heartbeats)
- syncope (transient, rapid-onset loss of consciousness)
- edema (accumulation of fluid in the spaces surrounding the organs and tissues of the body)
- constipation (difficult bowel movement)
- diarrhea
- flatulence (excessive gas formation in the stomach or intestines)
Rare (may affect up to 1 in 1000 people):
- bradycardia (slow heart rate)
- ileus (occlusion of the intestine)
- transient increase in liver enzymes
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
5. How to store ISKIDROP Keep this medicine out of the sight and reach of children.
Store in the original package to protect the medicine from light.
Do not refrigerate.
Do not use this medicine after the expiry date which is stated on the bottle after EXP. The expiry date refers to the last day of that month.
The shelf life after first opening the bottle is 1 month (write down the date of first opening in the space provided on the box).
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What ISKIDROP
- The active ingredient is nimodipine; 30 drops of solution (corresponding to 0.75 ml) contain 30 mg of nimodipine
- The other ingredients are: macrogolglycerol hydroxystearate and 96% ethyl alcohol (see section "ISKIDROP contains macrogolglycerol hydroxystearate and ethyl alcohol").
Description of what ISKIDROP looks like and contents of the pack
ISKIDROP is presented as a clear yellow solution which is administered in the form of oral drops. The solution is packaged in a 25 ml bottle equipped with a 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
ISKIDROP 30 MG / 0.75 ML ORAL DROPS, SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
30 drops of solution (corresponding to 0.75 ml) contain: Active ingredient: 30 mg nimodipine.
For excipients, see 6.1
03.0 PHARMACEUTICAL FORM
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
Unless otherwise prescribed, the recommended daily dose is 30 mg 3 times (30 drops of solution 3 times).
In patients with severely impaired renal function (glomerular filtration
In case of severe renal and hepatic impairment, any side effects, such as lowering of blood pressure, may be more pronounced; in these cases, the dose should be reduced or discontinued if necessary.
In patients who develop adverse reactions the dose should be reduced as needed or treatment discontinued
In case of concomitant administration with inhibitors or activators of the CYP 3A4 system, dosage modulation may be necessary (see section "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 - corresponding to 60 drops of solution - 6 times a day, at 4-hour intervals).
ISKIDROP should be taken between meals, the drops diluted in a little water.
Do not take with grapefruit juice (see "Interactions" section).
The interval between single administrations should not be less than 4 hours.
04.3 Contraindications
ISKIDROP must not be administered during pregnancy or breastfeeding and in cases of hypersensitivity to the active substance or to any of the excipients.
ISKIDROP 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 its metabolism related to the first pass effect or its clearance. For this reason ISKIDROP should not be administered to patients. with severely impaired liver function (e.g. liver cirrhosis).
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 "Interactions").
04.4 Special warnings and appropriate precautions for use
Although there is no evidence that ISKIDROP treatment is associated with an increase in intracranial pressure, ISKIDROP should be used with caution in the presence of generalized cerebral edema or in conditions characterized by a marked increase in intracranial pressure.
ISKIDROP should also be used with caution in severely hypotensive patients (systolic blood pressure
In very elderly patients with multiple pathologies, in patients with severely impaired cardiovascular or renal function (glomerular filtration
Nimodipine is metabolised via the cytochrome P450 3A4 system. Drugs that both inhibit and induce this enzyme system may therefore modify the first pass effect (after oral administration) or the clearance of nimodipine (see section "Interactions").
Drugs which inhibit the cytochrome P450 3A4 system, and therefore may cause an increase in the plasma concentration of nimodipine, are, for example:
• Macrolide antibiotics (eg erythromycin)
• HIV protease inhibitors (eg ritonavir)
• Azole antifungals (eg ketoconazole)
• 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.
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 both inhibiting and inducing this enzyme system may therefore modify the first pass effect (after oral administration) or the clearance of nimodipine.
The extent and duration of this interaction must 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 "Contraindications").
Antiepileptic drugs inducing the cytochrome P450 3A4 system, such as phenobarbital, phenytoin or carbamazepine.
Previous chronic therapy with phenobarbital, phenytoin or carbamazepine markedly reduces the bioavailability of oral nimodipine. Therefore concomitant therapy with these drugs and oral nimodipine is contraindicated (see section "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 section "Posology and method of administration" ).
Macrolide antibiotics (e.g. erythromycin)
No interaction studies have been performed between macrolide antibiotics and nimodipine. Some macrolide antibiotics are known as 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 "Special warnings and precautions for" use ").
Although structurally belonging to the class of macrolide antibiotics, azithromycin is not an inhibitor of the cytochrome CYP 3A4 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 section "Special warnings and precautions for use").
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 metabolism related to the first pass effect (see section "Special warnings and precautions for use").
Nefazodone
No full-fledged studies have been conducted to investigate the potential interaction between nimodipine and nefazodone. This antidepressant drug is known as 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 section "Special warnings and precautions for" use ").
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, did not. was affected.
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 "Special warnings and precautions for use").
Cimetidine
Co-administration of nimodipine and cimetidine (an H2 blocker) may lead to an increase in the plasma concentration of nimodipine (see section "Special warnings and precautions for use").
Valproic acid
Co-administration of nimodipine and valproic acid (an anticonvulsant) may lead to an increase in the plasma concentration of nimodipine (see section "Special warnings and precautions for use").
Further interactions
The concomitant use 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 enhance the antihypertensive effect of drugs of this class administered simultaneously, such as, for example:
• diuretics
• beta blockers
• ACE inhibitors
• A1 antagonists
• other alpha-blocking calcium channel blockers
• PDE5 alpha-methyldopa inhibitors
However, 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 for zidovudine with a significant reduction in its volume of distribution and clearance.
Interactions between drug and food
Grapefruit juice
Grapefruit juice inhibits the oxidative metabolism of dihydropyridines.
The simultaneous intake of grapefruit juice and nimodipine increases the plasma concentration and the duration of its action, due to a decrease in its metabolism linked to the first pass effect or its clearance. As a consequence of this, the antihypertensive effect of nimodipine may be increased. This phenomenon may occur 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.
Cases in which an interaction has not been highlighted
Haloperidol
Co-administration of steady-state nimodipine to patients on individual 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 breastfeeding
ISKIDROP must not be administered during pregnancy or lactation (see section
"Contraindications").
In-Vitro Fertilization: In individual cases of in-vitro fertilization, calcium channel blockers have been associated with reversible biochemical changes in the sperm head, possibly resulting in reduced sperm function.
04.7 Effects on ability to drive and use machines
The ability to drive and use machines may be impaired due to the possible occurrence of dizziness.
04.8 Undesirable effects
Table 1 shows drug-related adverse reactions reported in several clinical trials with nimodipine under the indication "Prevention and therapy of ischemic neurological deficits related to cerebral vasospasm", sorted by frequency categories according to CIOMS III (in studies versus placebo 703 patients were treated with Nimodipine and 692 with placebo, in open-label studies 2,496 patients were treated with Nimodipine). Status August 31, 2005.
Table 2 shows the drug-related adverse reactions reported in several clinical trials with nimodipine under the indication "Prevention and therapy of ischemic neurological deficits", sorted by frequency categories according to CIOMS III (in studies versus placebo 1,594 patients were treated with Nimodipine and 1,558 with placebo, in open-label studies 8,049 patients were treated with Nimodipine; status 20 October 2005) and post-marketing data (status: October 2005).
Adverse reactions reported as "common" were observed with a frequency of less than 2%.
04.9 Overdose
Symptoms of intoxication which must be considered following acute overdose are: flushing of the face, headache; marked hypotension, tachycardia or bradycardia; gastrointestinal disturbances and nausea. Treatment: discontinue drug administration immediately.
Gastric lavage with the addition of charcoal could be considered as an emergency measure. In case of severe hypotension, dopamine or noradrenaline should be given intravenously.
Otherwise, therapy must be aimed at eliminating the main symptoms, as no specific antidote is known.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: calcium channel blocker; 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 brain barrier. In animal studies, nimodipine binds with high affinity and selectivity to L-type Ca ++ channels, thus 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 different 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.
Researches conducted in patients suffering from acute cerebrovascular disorders, have allowed to highlight 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 theft phenomena.The use of nimodipine results in a significant reduction in ischemic neurological deficits and in mortality following vasospasm from subarachnoid haemorrhage 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 assessment of the overall clinical impression, the assessment of individual disorders, the observation of behavior and psychometric tests.
05.2 Pharmacokinetic properties
Absorption
The active substance nimodipine, administered orally, is practically completely absorbed.
The unchanged active substance and its first metabolites, after the first step, 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. infusion. 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 exceeds 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 by dehydrogenation of the dihydropyridine ring and oxidative deesterification of the ester, which represents the further important metabolic steps with the hydroxylation of ethyl groups 2 and 6 and glucuronidation.
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 emunctorium, 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
Preclinical data based on conventional studies at single and repeated doses reveal no special risks for humans with respect to toxicity, genotoxicity, carcinogenesis and fertility for both males and females. In pregnant rats, doses equal to or greater than 30 mg / kg / day inhibited fetal growth causing a decrease in fetal weight. A dose of 100 mg / kg / day was lethal 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 equal to or greater than 10 mg / kg / day. These results were not confirmed by subsequent studies.
Acute toxicity
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 one-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 Toxicology Studies
Fertility studies in rats
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 pregnant rats did not reveal any harmful effects while doses 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 doses 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 have not been confirmed in 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 the 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 a number of mutagenicity studies which did not show significant mutagenic effects of gene induction and chromosomal mutations.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Macrogolglycerol hydroxystearate, Ethanol (96%)
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products
06.3 Period of validity
In intact packaging: 3 years
After first opening the bottle 1 month
06.4 Special precautions for storage
Store in the original package to protect the medicine from light. Do not refrigerate.
06.5 Nature of the immediate packaging and contents of the package
25 ml bottle of amber glass, inserted dropper and screw cap
06.6 Instructions for use and handling
Do not dispose of the bottle in the environment after use.
07.0 MARKETING AUTHORIZATION HOLDER
MDM S.p.A., Viale Papiniano, 22 / b - 20123 Milan
08.0 MARKETING AUTHORIZATION NUMBER
ISKIDROP 30 mg / 0.75 ml oral drops, solution: AIC n. 038071015
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
May 2008
10.0 DATE OF REVISION OF THE TEXT
July 2010
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