| Section 4.2 -
Expanded information content has now been included for aneurysmal subarachnoid haemorrhage, describing details of the possible necessity for dose adjustments/discontinuation after the development of adverse reactions, and/or after co-administration of CYP 3A4 inhibitors/inducers, and in patients with severely disturbed liver function. A description of the effect of disturbed liver function on the bioavailability and metabolism of nimodipine, and on the severity of possible effects/side effects in patients, has been added. Updated tablet administration information and a warning regarding the avoidance of the ingestion of grapefruit juice are included.
Section 4.3 -
Addition of new contraindications: 1) patients suffering from known hypersensitivity to nimodipine or to any of the tablet excipients; and, 2) use of nimodipine in combination with rifampicin and certain antiepileptic drugs (e.g., phenobarbital), due to concerns regarding reduced efficacy of Nimotop tablets after drug co-administration.
Section 4.4 -
Expanded information content has now been included, describing a recommendation to closely monitor intracranial pressure in patients suffering from (generalised) cerebral oedema or raised intracranial pressure, after treatment with Nimotop. Cautionary statements have been added regarding: 1) hypotensive patients; and, 2) cytochrome P450-mediated metabolism of nimodipine, and the influence on nimodipine metabolism of other drugs known to either inhibit (e.g., certain antidepressants, antibiotics, amongst other types of drug), or induce, the cytochrome P450 system, and possible resultant effects on nimodipine plasma levels. A statement has been added describing the necessity for monitoring of blood pressure upon co-administration of such drugs and for consideration of a dose adjustment in such cases.
Section 4.5 -
Substantial modifications have been made to this section, such that it has now been re-written and re-ordered. Overall, the current information content, regarding possible drug interactions and their likely effects on nimodipine metabolism, the necessity for patient monitoring, dose adjustment, etc., has been either maintained or expanded. More specifically, the co-administration of oral nimodipine and rifampicin or cytochrome P450 3A4 system-inducing antiepileptic drugs (e.g., phenytoin) is now contraindicated, and additional information has been added for the drugs azithromycin, quinupristin and dalfopristin. The current information regarding nimodipine and cytochrome P450 3A4, and blood pressure lowering drugs, has also been updated and extra information has been supplied concerning the possible effects (and duration of effect) on blood pressure after the ingestion of grapefruit juice. An additional statement has been added detailing certain drugs (e.g., diazepam, warfarin, etc.) that show no apparent interaction with oral nimodipine upon co-administration.
Section 4.6 -
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Further information has been provided detailing the absence of well-controlled clinical studies in pregnant women and the occurrence of reproductive toxicity in animal studies. Additional cautionary information has also been supplied regarding treatment with Nimotop and lactation and breast-feeding, and the association (in certain single-cases) of calcium antagonists with a possible reversible negative effect on sperm function/in vitro fertilization.
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Section 4.8 -
The information content has now been expanded to include more specific information on possible side effects and an indication of the observed frequency of occurrence has been assigned for each. Overall, these details have now been sub-divided and listed by affected body system (e.g., cardiac disorders). Various side-effects not listed previously are now shown, including: certain immune system disorders; unspecific cerebrovascular symptoms; unspecific cardiac arrhythmias; unspecific cardiovascular symptoms, including uncommon vasodilatation; unspecific gastrointestinal and abdominal symptoms; and, hepatobiliary disorders. Furthermore, the frequency of occurrence of thrombocytopenia has been amended from ‘very rare’ to ‘uncommon’, and that of ileus from ‘very rare’ to ‘rare’; in addition, ‘dizziness’ has been deleted from the amended list of side-effects.
Section 4.9 - The level of information has now been significantly expanded to detail: anticipated symptoms of acute overdosage (e.g., marked lowering of blood pressure, etc.); immediate treatment discontinuation in the event of acute overdosage; and, a description of emergency therapeutic measures to be used (as governed by symptoms), such as gastric lavage with charcoal, etc
Section 5.1 -
This section has been updated by the addition of the ATC code and a statement quantifying the ability of nimodipine to prevent/reduce vasoconstrictions provoked in vitro by certain vasoactive substances/blood (products), by up to 75 %.
Section 5.2 -
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Overall, the information content of this section remains largely unchanged, except data points describing first pass metabolism, bioavailability and plasma protein binding have undergone minor amendments in line with current knowledge. Further to this, the text has been re-phrased slightly and some extra information has been included, detailing the tissue-availability of Nimotop Solution for Infusion, and, the distribution volume and the total systemic clearance, in addition to peak plasma concentration and the area under the curve, after i.v. administration of nimodipine. A statement describing the significant role of the cytochrome P450 3A4 system in the metabolic elimination of nimodipine is also included.
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Section 5.3 -
The amount of information in this section has been expanded overall, to include a statement detailing the absence of special hazards for humans, based on the results of conventional pre-clinical dosing studies of (geno)toxicity, carcinogenicity and fertility. Further specific information is provided, describing possible dose-related negative effects on foetal growth/weight, and of embryolethality at a higher dose, in pregnant rats. Other information describes single-case equivocal evidence of dose-related teratogenicity in rabbits that was not subsequently reproduced and unconfirmed delayed physical development/mortality in a single rat study
Section 9 -
Dates amended from, ’23 February 1989/11 July 2000’, to, ’23 February 1989/23 November 2003’.
Section 10 -
Date amended from, ’August 2005’, to, ‘October 2007’.
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