Nimotop

Nimotop

nimodipine

Manufacturer:

Bayer HealthCare Pharma

Distributor:

DKSH
Full Prescribing Info
Contents
Nimodipine.
Action
Calcium antagonist.
Nimodipine is a calcium antagonist belonging to the 1,4-dihydropyridine group. On account of its highly lipophilic nature, the substance easily penetrates the blood-brain barrier. In animal studies, nimodipine binds with high affinity and selectivity to calcium-ion channels of the L-type, thus blocking the influx of calcium ions through the membrane. In pathological states associated with the increased influx of calcium ions into the nerve cells eg, cerebral ischemia, nimodipine is believed to improve the stability and functional capacity of these cells.
Investigations carried out in patients with acute cerebral circulatory disturbances have shown that nimodipine dilates the cerebral vessels and increases cerebral circulation, the increased perfusion being generally more pronounced in areas of the brain with preliminary damage and restricted circulation than in healthy areas. The improvement is particularly noticeable in patients with cerebral vasospasm after subarachnoid haemorrhage. Nimodipine produces significant reductions in ischemic neurological deficits caused by vasospasm and in mortality.
Selective blockade of calcium-ion channels in certain areas of the brain eg, the hippocampus and cortex may possibly explain the positive effect of nimodipine on learning and memory deficits observed in various animal models. The same molecular mechanism probably underlies the cerebral vasodilative and blood flow-promoting effect of nimodipine observed in animals and humans. The exact mechanism by which the molecular effects of nimodipine produce the improvements in disturbed brain function that have been demonstrated in neurophysical and clinical test models will be the subject of future investigations.
Pharmacokinetics: Absorption: The orally administered active substance, nimodipine, is practically completely absorbed. The unchanged active substance and its early first-pass metabolites are detected in plasma as little as 10-15 min after ingestion of the tablet. Following multiple-dose oral administration (3 x 30 mg/day), the mean peak plasma concentrations (Cmax) are 7.3-43.2 ng/mL in elderly individuals, these being reached after 0.6-1.6 hrs (tmax). The peak plasma concentration and the area under the curve increase proportionally to the dose up to the highest dose under test (90 mg).
Using continuous infusions of 0.03 mg/kg/hr, mean steady-state plasma concentrations of 17.6-26.6 ng/mL are achieved. After IV bolus injections, the plasma nimodipine concentrations fall biphasically with half-lives of 5-10 min and about 60 min. The distribution volume (Vss, 2-compartment model) for IV administration is calculated to be 0.9-1.6 L/kg/body weight. The total (systemic) clearance is 0.6-1.9 L/hr/kg.
Protein-Binding and Distribution: Nimodipine is 97-99% bound to plasma proteins. Nimodipine added to whole blood is roughly equally distributed between the erythrocytes and the plasma. In animal studies, nimodipine has been shown to penetrate the placental barrier. In lactating rats it has also been shown to pass into the milk. It is probable that both these processes also occur in humans, although no data is as yet available.
After oral and IV administration, nimodipine can be detected in the CSF in concentrations about 0.5% of the measured plasma concentrations. These correspond roughly to the free concentration in plasma.
Metabolism, Elimination and Excretion: Nimodipine is eliminated metabolically, mainly by dehydrogenation of the dihydropyridine ring and oxidative ester cleavage. Oxidative ester cleavage, hydroxylation of the 2- and 6-methyl groups and glucuronidation as a conjugation reaction are further important metabolic steps. The 3 primary metabolites occurring in plasma show no or only therapeutically unimportant residual activity.
Effects on liver enzymes by induction or inhibition are unknown. In humans, the metabolites are excreted about 50% renally and 30% in the bile.
The elimination kinetics are linear. The half-life for nimodipine is between 1.1 and 1.7 hrs. The terminal half-life of 5-10 hrs is of no importance for establishing the dosage interval in the package insert.
Bioavailability: On the basis of the high metabolization during the first-pass through the liver (about 85-90%) the absolute bioavailability is 10-15%.
Toxicology: Acute Toxicity (LD50): See table.

Click on icon to see table/diagram/image
Chronic Toxicity: The systemic tolerability of nimodipine at doses up to 6.25 mg/kg/day was studied in dogs in a study lasting 1 year. Doses up to 2.5 mg/kg proved harmless; 6.25 mg/kg produced slight though reversible ECG changes as a result of disturbances to the myocardial blood flow. However, no histopathological changes in the heart or in other organs were detected at this dose. Rats given daily doses of nimodipine up to about 90 mg/kg/day in feed for a period of 2 years tolerated these doses without harm.
Oncogenic and Mutagenic Potential: A lifetime study in which rats received nimodipine at doses of up to 1800 ppm (about 90 mg/kg/day) in their feed for 2 years yielded no evidence of an oncogenic potential. Similarly, a long-term study in which mice received 500 mg/kg/day orally for 21 months produced no evidence that nimodipine has an oncogenic potential.
Nimodipine has been the subject of extensive mutagenicity testing. Tests for the induction of genetic and chromosomal mutations have yielded no relevant evidence of mutagenic effects.
Teratogenicity: Reproduction Toxicity: The fertility of male and female rats and subsequent generations was unimpaired at doses up to 30 mg/kg/day.
Administration of 10 mg/kg/day to pregnant rats during embryogenesis showed no harmful effects. Doses ≥30 mg/kg/day inhibited growth, causing reduced fetal weight, and at 100 mg/kg/day increased numbers of embryos died in utero. No teratogenic effects were observed.
Embryotoxicity studies in rabbits with doses up to 10 mg/kg/day orally yielded no evidence of teratogenic or other embryotoxic effects.
To investigate perinatal and postnatal development, studies were conducted in rats with doses up to 30 mg/kg/day. In 1 study, increased perinatal and postnatal mortality and delayed physical development were observed with ≥10 mg/kg/day. These findings were not confirmed in subsequent studies.
No findings are available from use during pregnancy and lactation in humans.
Indications/Uses
Prophylaxis and treatment of ischemic neurological deficits caused by cerebral vasospasm after subarachnoid haemorrhage.
Treatment of impaired brain function in old age with pronounced symptoms eg, impaired memory, drive and concentration, and mood lability.
Before treatment with Nimotop began, it should be established that the symptoms are not caused by an underlying disease requiring specific treatment.
Dosage/Direction for Use
Dosage Including Tolerance Dose: According to Indication: Unless prescribed otherwise, the following dosage guidelines are recommended:
Prophylaxis and Treatment of Ischemic Neurological Deficits caused by Cerebral Vasospasm after Subarachnoid Haemorrhage: Continuous IV Infusion: At the start of the treatment, nimodipine 1 mg (5 mL infusion solution)/hr for 2 hrs (about 15 mcg/kg body weight/hr). If the tolerability is good, and particularly, if there is no severe reduction in blood pressure, the dose is increased after 2 hrs to 2 mg (10 mL infusion solution)/hr (about 30 mcg/kg body weight/hr). Patients whose body weights are distinctly <70 kg or who have labile blood pressure can start with a dose of 0.5 mg (2.5 mL infusion solution)/hr. If symptoms of intolerance appear, the dose should be reduced or, if necessary, the treatment discontinued.
In cases of severely disturbed kidney or liver function, particularly in cirrhosis of the liver, the effects and side effects eg, the reduction in blood pressure, may be more pronounced. In such cases, the dose should, if necessary, be reduced in accordance with blood pressure monitoring and the ECG.
After preliminary administration of nimodipine infusion solution for 5-14 days, a dose of 6 x 2 tabs (6 x 60 mg)/day should be given for 7 days.
Intracisternal Instillation: 20 mL of a dilute solution of Nimotop: Nimotop infusion 1 mL and Ringer solution 19 mL. This dilution must be used immediately after preparation.
Treatment of Impaired Brain Function: Elderly: Recommended Daily Dose: 3 x 1 tab (3 x 30 mg).
No tolerance doses are known.
Administration Route Including Descriptions of Usage and Incompatibility:
Continuous IV Infusion: Nimotop is administered as a continuous IV infusion via an infusion pump in the bypass with approximately 100 mL/day infusion solution: glucose 5%, Lactated Ringer's solution, Lactated Ringer's solution with magnesium, dextran 40 solutions, poly(O-2-hydroxyethyl) starch 6%, AKE 1100, Fresenius AG (amino acid and electrolyte solution for parenteral feeding), human albumin 5% or with blood via a central catheter. Nimotop infusion solution must not be mixed with any other drug.
Administration of Nimotop should be continued during anesthesia, surgery and angiography.
Since the active substance of Nimotop is absorbed by polyvinyl chloride (PVC), only infusion pumps with polyethylene (PE) infusion tubing must be used.
Intracisternal Instillation: During surgery, a freshly prepared dilute solution warmed to body temperature can be instilled intracisternally. This dilute Nimotop solution must be used immediately after preparation.
Tablet: In general, the tablets should be swallowed whole with a little liquid, independent of meal times. The interval between each administration should not be less than 4 hrs.
Duration of Use: For Prophylaxis and Treatment of Ischemic Neurological Deficits Caused by Cerebral Vasospasm After Subarachnoid Haemorrhage:
Prophylactic Administration: IV treatment should start not later than 4 days after haemorrhage and be continued during the period of maximum risk of a vasospasm ie, up to 10-14 days after subarachnoid haemorrhage.
After the end of infusion treatment, oral administration of 6 x nimodipine 60 mg/day at 4-hr intervals for a further 7 days is recommended.
Therapeutic Administration: If ischemic neurological disturbances caused by a vasospasm after a subarachnoid haemorrhage are already present, treatment must start as soon as possible and be continued for at least 5 days up to a maximum of 14 days.
Thereafter, oral administration of 6 x nimodipine 60 mg/day at intervals of 4 hrs for 7 days is recommended.
If during a therapeutic or prophylactic administration of Nimotop, the source of the haemorrhage is operated on, IV treatment with Nimotop should be continued postoperatively for at least 5 days.
Treatment of Impaired Brain Function: Elderly: If Nimotop tablet is taken over a period of several months, it should be assessed whether there are indications for treatment with this product that still exists.
Overdosage
Symptoms: Symptoms that must be anticipated as a result of acute overdosage are facial redness (flush), headache, marked lowering of the blood pressure, tachycardia or bradycardia, gastrointestinal discomfort and nausea.
Treatment: In acute overdosage, treatment with Nimotop must be discontinued immediately. Gastric lavage with addition of charcoal should be considered as an emergency therapeutic measure. If there is a marked decrease in blood pressure, dopamine of noradrenaline should be administered IV. As no specific antidote is known, subsequent treatment for other side effects should be aimed at the most prominent symptoms.
Contraindications
If the water content of the brain tissue is elevated (generalized cerebral edema) or if there is an appreciable elevation of intracranial pressure, Nimotop must be used with caution.
In very old multimorbid patients, patients with severely impaired kidney function (glomerular filtration rate <20 mL/min), and in those with severely impaired cardiovascular function the need for treatment with Nimotop should be carefully considered and follow-up examination should be carried out regularly.
Special Precautions
Caution is required in severely hypotensive patients (systolic blood pressure <90 mm Hg).
Nimotop tablet must not be administered to patients with severely impaired liver function (eg, cirrhosis of the liver).
Use in pregnancy & lactation: In view of its indication area, Nimotop is not used during pregnancy or lactation.
Use In Pregnancy & Lactation
In view of its indication area, Nimotop is not used during pregnancy or lactation.
Side Effects
Adverse reactions are generally mild and transient, occur infrequently and usually at the beginning of treatment.
Oral Administration: A feeling of warmth or heat sensation, reddening of the skin, a lowering of the blood pressure (especially when the initial value is elevated) and increase in heart rate, dizziness, headache, gastrointestinal discomfort, feeling of weakness, peripheral edema. In a few patients, symptoms of overactivation of the CNS may occur eg, sleeplessness, increased motor agitation, excitation, aggregation and sweating. Hyperkinesia and depressive mood may occur in isolated cases.
IV Administration: Undesirably severe lowering of the blood pressure, particularly when the initial value is elevated, headache, elevation of transaminases, alkaline phosphatase and γ-glutamyl transferase (α-GT), deterioration of kidney function with increased BUN and/or serum creatinine, sweating, reddening of the face (flush) and venous inflammation (if undiluted, Nimotop is infused into peripheral veins).
It must be remembered that the formulation contains 23.7 volume-percent alcohol.
Drug Interactions
In patients taking drugs that lower the blood pressure, Nimotop may intensify the blood pressure-lowering effect of the concomitant medication.
The simultaneous administration of cimetidine can lead to an increase in the plasma nimodipine concentration.
Combination with other calcium antagonists (eg, nifedipine, diltiazem, verapamil) or with α-methyldopa must be avoided if possible. However, if a combination of this type proves imperative, the patient must be monitored particularly carefully. Simultaneous IV administration of β-blockers can lead to mutual potentiation of negative inotropic effects and even to decompensated heart failure.
Kidney function can deteriorate during concomitant treatment with potentially nephrotoxic drugs (eg, aminoglycosides and/or cephalosporins in combination with furosemide) and in patients whose kidney function is already impaired. Kidney function must be monitored carefully in such cases. If there is a deterioration of kidney function, discontinuation of the treatment should be considered.
It is important to note that, since the solvent is alcoholic, interactions with alcohol-incompatible drugs can occur.
Adequate information is not available on the simultaneous use of nimodipine with neuroleptics, antidepressants, tranquilizer and cardiac glycosides.
Storage
Tablet: Nimotop film-coated tablets are stable for up to 5 years under normal storage conditions.
Infusion solution: Nimotop infusion solution has a good stability, but is somewhat sensitive to light, and therefore must not be used in direct sunlight. If appropriate, infusion pumps and tubing must be protected with opaque coverings, or black, brown, yellow or red infusion lines can be used. However, in diffuse daylight or artificial light Nimotop infusion solution can be used for up to 10 hrs without protection from light.
ATC Classification
C08CA06 - nimodipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.
Presentation/Packing
Film-coated tab 30 mg x 30's. Infusion 10 mg/50 mL x 1's.
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