Symptoms of intoxication
Symptoms of acute overdosage to be anticipated are marked lowering of the blood pressure, tachycardia, bradycardia and (after oral administration) gastro-intestinal complaints and nausea.
Treatment of intoxication
In the event of acute overdosage, treatment with Nivas Forte must be discontinued immediately. Emergency measures should be governed by the symptoms. If the substance was ingested orally, gastric lavage with addition of charcoal should be considered as an emergency therapeutic measure. If there is a marked fall in blood pressure, dopamine or noradrenaline can be administered intravenously. As no specific antidote is known, subsequent treatment for other side effects should be aimed at the most prominent symptoms.
Nimodipine should not be administered to patients during or within one month of a myocardial infarction or an episode of unstable angina.
Nivas Forte solution reacts with polyvinylchloride (PVC) and should not be allowed to come in contact with PVC. Nivas Forte solution must not be added to an infusion bag or bottle and must not be mixed with other drugs. Crystallization was observed during co-infusion of Nivas Forte solution with 2.5% xylite in 0.4% sodium chloride solution (Summafusin), Aminosteril (Fresenius) and Ringer's solution DAB7.
The frequencies of ADRs reported with nimodipine summarized in the tables below are based on clinical trials with nimodipine in the indication aSAH sorted by CIOMS III categories of frequency (placebo-controlled studies: nimodipine N = 703; placebo N = 692; uncontrolled studies: nimodipine N = 2496; status: 31 Aug 2005). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Frequencies are defined as:
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)
| System Organ Class (MedDRA) | Uncommon | Rare |
| Blood and the lymphatic system disorders | Thrombocytopenia | |
| Immune system disorders | Allergic reaction Rash | |
| Nervous system disorders | Headache | |
| Cardiac disorders | Tachycardia | Bradycardia |
| Vascular disorders | Hypotension Vasodilatation | |
| Gastrointestinal disorders | Nausea | Ileus |
| Hepato-biliary disorders | Transient increase in liver enzymes | |
| General disorders and administration site conditions | Injection and infusion site reactions Infusion site (thrombo-) phlebitis |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. However, several preclinical findings may be of relevance to the prescribing physician. In chronic repeat dose toxicity studies in dogs, doses of 1 and 2.5 mg/kg/day were shown to be tolerated without adverse effect. However, at the higher dose of 6.25 mg/kg/day significant changes in ECGs were noted due to disturbances in myocardial blood flow, but there was no indication of histopathological damage to the heart. In pregnant rats, doses of 30 mg/kg/day and higher inhibited fetal growth and resulted in reduced fetal weights. At 100 mg/kg/day embryolethality occurred. No evidence of teratogenicity was observed. In rabbits, equivocal evidence of teratogenicity was seen in one study at doses up to 10 mg/kg/day. In two subsequent studies (one at 30 mg/kg/day), these findings were not reproduced. In one peri-postnatal study in rats, mortality and delayed physical development were observed at doses of 10 mg/kg/day and higher. The findings were not confirmed in subsequent studies.
Nimodipine is indicated for the treatment of ischaemic neurological deficits following aneurysmal subarachnoid haemorrhage.
Pharmacotherapeutic group: selective calcium channel blockers with mainly vascular effect, dihydropyridine derivatives, ATC Code: C08CA06
Nimodipine is a dihydropyridine calcium channel blocker with particular cerebrovascular effect. Nimodipine increases cerebral perfusion, particularly in poorly perfused areas, by arterial dilatation, an effect which is proportionately greater in smaller than in larger vessels.
Vasoconstrictions provoked in vitro by various vasoactive substances (e.g., serotonin, prostaglandins and histamine) or by blood and blood degradation products can be prevented or reduced by up to 75 % by nimodipine.
The intravenous Nivas Forte solution is 100% available to the tissues as the peripheral venous blood takes the drug to the lungs and heart and from there to all organs.
Absorption
After oral ingestion, absorption is rapid. Peak plasma concentrations are observed 30 to 60 minutes following oral administration. Despite high gastrointestinal absorption of nimodipine, the absolute bioavailability is 5 - 15 %, which is attributed to extensive first pass metabolism (about 85 - 95 %).
Distribution
The distribution volume (Vss, 2 compartment model) for i.v. administration is calculated to be 0.9 - 2.3 l/kg body weight. The total (systemic) clearance is 0.8 - 1.6 l/h/kg. Nimodipine is 97 - 99 % bound to plasma proteins.
Biotransformation
The cytochrome P450 3A4 system plays a major role in the metabolic elimination of nimodipine. Nimodipine is eliminated as metabolites, mainly by dehydrogenation of the dihydropyridine ring and oxidative O-demethylation. Oxidative ester cleavage, hydroxylation of the 2- and 6-methyl groups, and glucuronidation as a conjugation reaction are other important metabolic steps. The three primary metabolites occurring in plasma show no or only therapeutically negligible residual activity.
Elimination
Effects on liver enzymes by induction or inhibition are unknown. In humans the metabolites are excreted about 50 % renally and 30 % in the bile.
Linearity/non-linearity
For oral administration, the peak plasma concentration and the area under the curve increase proportionally to the dose up to the highest dose under test (90 mg). The elimination kinetics are linear. The half-life for nimodipine is between 1.1 and 1.7 hours. The terminal half-life is 5-10 hours, and is not relevant for establishing the recommended dosing interval for the medicinal product.
Nivas Forte should not be used in patients with traumatic subarachnoid haemorrhage as a positive benefit to risk ratio has not been established and the specific patient groups that might benefit cannot be identified for this indication.
Nivas Forte solution should be used with care when cerebral oedema or severely raised intracranial pressure are present. Although treatment with Nivas Forte has not been shown to be associated with increases in intracranial pressure, close monitoring is recommended in these cases or when the water content of the brain tissue is elevated (generalised cerebral oedema).
Nivas Forte solution must be used with caution in hypotensive patients (systolic blood pressure lower than 100 mm Hg).
Decreased drug clearance may occur in cirrhotic patients receiving Nivas Forte and, therefore, close monitoring of blood pressure is recommended in these patients.
This medicinal product contains 1 mmol (23 mg) sodium per 50 ml bottle or 5.1 mmol (115 mg) sodium per 250 ml bottle. To be taken into consideration by patients on a controlled sodium diet.
Patients with known renal disease and/or receiving nephrotoxic drugs should have renal function monitored closely during intravenous treatment with Nivas Forte solution.
Nimodipine is metabolised via the cytochrome P450 3A4 system. Drugs which are known inhibitors of the cytochrome P450 3A4 system and, therefore, may lead to increased plasma concentrations of nimodipine are macrolide antibiotics (e.g. erythromycin), anti-HIV protease inhibitors (e.g. ritonavir), azole antimycotics (e.g. ketoconazole), the antidepressants nefazodone and fluoxetine, quinupristin/dalfopristin, cimetidine and valproic acid .
Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction in the nimodipine dose should be considered.
This medicinal product contains 23.7 vol % ethanol (alcohol), i.e. up to 50 g per daily dose (250 ml). This may be harmful for those suffering from alcoholism or impaired alcohol metabolism and should be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines.
In theory, the possibility of the occurrence of the side-effect dizziness may impair the patient's ability to drive or operate machinery. However, this is unlikely to be of clinical relevance in patients receiving Nivas Forte Solution.
Posology
Recommended dose - Aneurysmal Subarachnoid Haemorrhage
For the first two hours of treatment 1 mg of nimodipine, i.e. 5 ml Nivas Forte solution, (about 15 μg/kg bw/h), should be infused each hour via a central catheter. If it is well tolerated, the dose should be increased after two hours to 2 mg nimodipine, i.e. 10 ml Nivas Forte solution per hour (about 30 μg/kg bw/h), providing no severe decrease in blood pressure is observed.
Patients of body weight less than 70 kg or with unstable blood pressure should be started on a dose of 0.5 mg nimodipine per hour (2.5 ml of Nivas Forte solution), or less if necessary.
Duration of treatment
Aneurysmal subarachnoid haemorrhage
Intravenous treatment should begin as early as possible after neurological deficit occurs due to arterial spasm, post subarachnoid haemorrhage. This should continue for at least five days up to a maximum of 14 days.
In the event of surgical intervention during treatment, administration of nimodipine should be continued (dose as above) for at least five days.
Nivas Forte solution may be used with or without pre-treatment with Nivas Forte tablets. In the event of Nivas Forte tablets and Nivas Forte solution being administered sequentially the total duration of treatment should not exceed 21 days. Nivas Forte solution should not be administered for longer than 14 days. Nivas Forte solution and tablets should not be used concomitantly.
Traumatic subarachnoid haemorrhage
Not recommended as a positive benefit to risk ratio has not been established.
Paediatric Population
The safety and efficacy of Nivas Forte in patients under 18 years of age have not been established.
Method of administration
Nivas Forte solution is administered as a continuous I.V. infusion via a central catheter using an infusion pump. It should be connected to a three-way stopcock using the infusion line provided. The three-way stopcock should be used to connect the Nivas Forte polyethylene tube with the co-infusion line and the central catheter. (The stopcock must allow for concomitant flow of the Nivas Forte solution and a co-infusion solution.) Nivas Forte solution must be administered with a co-infusion running at a rate of 40 ml/hr of either sodium chloride 0.9%, glucose 5%, Ringer's lactate solution, lactated Ringer's solution with magnesium, dextran 40, HAES® (poly[O-2-hydroxyethyl]) starch 6%, human albumin 5%, blood or mannitol 10% in a ratio of about 1:4 (Nivas Forte:co-infusion), which is connected to the second port of the three-way stopcock prior to its connection with the central line catheter.
Nivas Forte solution must not be added to an infusion bag or bottle and must not be mixed with other drugs.
Nivas Forte solution may be used during anaesthesia, angiography or surgical procedures.
The only plastic materials suitable for use are polyethylene or polypropylene. Nivas Forte solution is compatible with glass infusion bottles and infusion packs made of polyethylene (e.g., Polyfusor, Boots).
The solution when in the syringe must be protected from direct sunlight during administration, but it is stable in diffuse daylight and artificial light for up to 10 hours. Nivas Forte solution should be infused using a glass or rigid plastic (polyethylene or polypropylene) syringe and giving set (Gillette Sabre syringe; BD plastipak syringe; Monoject disposable syringe, Sherwood Medical Ltd; Combidyn tubes, Braun; Nitrocassette giving set, Imed Ltd.). Nivas Forte solution is incompatible with infusion bags and any giving sets made of PVC (e.g., Viaflex, Travenol; Steriflex, Boots).
To penetrate the coated injection stoppers correctly, fine acute injection needles are recommended. DO NOT use large-core infusion needles, since this may result in cracked or bruised stoppers and the stoppers may be forced into the vial.
