Nimotop 30mg film-coated tablets

BP24001, REC32348

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Text in red strikethrough = deleted text

6.3         Shelf Life

5 years.Folding boxes containing PP/Aluminium foil blister packs: 5 years

Folding boxes containing PVC/PVDC/Aluminium foil blister packs: 4 years

10.      DATE OF REVISION OF THE TEXT

September 2022March 2024

BP22036, REC30610

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Text in red with strikethrough = deleted text

6. Contents of the pack and other information

[…]

Marketing Authorisation Holder:

Bayer Limited, 1st Floor, The Grange Offices, The Grange, Brewery Road, Stillorgan, Co. Dublin, A94 H2K7, The Atrium, Blackthorn road, Dublin 18, Ireland

[…]

This leaflet was last revised in: August 2021September 2022

BP22036, REC30610

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Text in colour = added text

Text in red with strikethrough = deleted text

7. MARKETING AUTHORISATION HOLDER

Bayer Limited

1^st Floor

The Grange Offices

The Grange

Brewery Road

Stillorgan

Co. Dublin

A94 H2K7

The Atrium

Blackthorn Road

Dublin 18

Ireland

10. DATE OF REVISION OF THE TEXT

 November 2018September2022

BP22036, REC30610

Note:

Text in blue = added text

Text in red with strikethrough = deleted text

6. Contents of the pack and other information

[…]

Marketing Authorisation Holder:

Bayer Limited, 1st Floor, The Grange Offices, The Grange, Brewery Road, Stillorgan, Co. Dublin, A94 H2K7, The Atrium, Blackthorn road, Dublin 18, Ireland

[…]

This leaflet was last revised in: January 2021September 2022

BP22036, REC30610 + REC19543 – PA number reformat Please note deletion of space between PA and 1410

Note:

Text in colour = added text

Text in red with strikethrough = deleted text

7. MARKETING AUTHORISATION HOLDER

 Bayer Limited

1^st Floor

The Grange Offices

The Grange

Brewery Road

Stillorgan

Co. Dublin

A94 H2K7

The Atrium

Blackthorn Road

Dublin 18

Ireland

8. MARKETING AUTHORISATION NUMBER

PA1410/030/001

10. DATE OF REVISION OF THE TEXT

January 2021September2022

BP22069, BEC13137, 17119, 18310 - Excipient Guideline and QRD update

BEC13137, 17119, 18310 - Excipient Guideline and QRD update

In the previous version, in Section 8 - Marketing Authorisation Holder, the Maltese MA number was included with the HPRA PA number in error.

The Maltese MA number has now been deleted. No other changes were made to the text.

In Section 7, "Ireland" has been added to the MAH address.

In Section 8, the HPRA PA number has been reformatted as follows: PA1410/030/001. A Maltese licence number is also added: AA639/02402.

In section 4.2

·         The subheading Special populations

·         The following was inserted

“Paediatric population

Safety and efficacy of nimodipine in patients under 18 years of age have not been established.”

In section 4.8 information on Reporting of suspected adverse reactions was introduced.

The date of revision was updated

Aneurysmal subarachnoid haemorrhage

Dosage: Posology:

…………….

Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of nimodipine due to a decreased first-pass capacity and a reduced metabolic clearance. The effects and side-effects, e.g. reduction in blood pressure, may be more pronounced in these patients.

In such cases the dose should be reduced (depending on the blood pressure) or, if necessary, discontinuation of the treatment should be considered.

Upon co-administration with cytochrome P450 3A4 inhibitors or inducers, a dose adaption may be necessary (see sections 4.4 and 4.5).

Administration: Method of administration:

…………….

Patients with hepatic impairment

Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of nimodipine due to a decreased first-pass capacity and a reduced metabolic clearance. The effects and side-effects, e.g. reduction in blood pressure, may be more pronounced in these patients.

In such cases the dose should be reduced (depending on the blood pressure) or, if necessary, discontinuation of the treatment should be considered.

Section 4.3 Contraindications

Known Nimodipine must not be used in case of hypersensitivity to Nimodipine the active

substance of or any of the excipients.

Nimodipine should not be administered to patients during or within one month of a myocardial infarction or an episode of unstable angina.

The use of nimodipine in combination with rifampicin is contraindicated as the efficacy of Nimotop tablets nimodipine could be significantly reduced when concomitantly administered. (See section 4.5 Interaction with other medicinal products and other forms of interaction).

The concomitant use of oral nimodipine and the antiepileptic drugs, phenobarbital, phenytoin or carbamazepine is contraindicated as the efficacy of Nimotop tablets nimodipine could be significantly reduced (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Section 4.4: Special warnings and precautions for use

Nimotop tablets should be used with care when cerebral oedema or severely raised intracranial pressure are present. Although treatment with Nimotop nimodipine 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).

Caution is required in patients with hypotension (systolic blood pressure lower than 100 mm Hg).

Decreased drug clearance may occur in cirrhotic patients receiving Nimotop and therefore close monitoring of blood pressure is recommended in these patients.

In patients with unstable angina or within the first 4 weeks after acute myocardial infarction, physicians should consider the potential risk (e.g. reduced coronary artery perfusion and myocardial ischemia) versus the benefit (e.g. improvement of brain perfusion).

Nimodipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or induce this enzyme system may, therefore, alter the first pass or the clearance of nimodipine (see section 4.5 Interaction with other medicinal products and other forms of interaction and Section 4.2 Posology and method of administration / Patients with hepatic impairment).

Drugs which are known inhibitors of the cytochrome P450 3A4 system and, therefore, may lead to increased plasma concentrations of nimodipine are, e.g.:

·         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.

Section 4.5: Interaction with other medicinal products and other forms of interaction

Nimotop tablets should not be administered concomitantly with Nimotop solution.

Drugs that affect 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 either inhibit or induce this enzyme system may, therefore, alter the first pass or the clearance of nimodipine (see section 4.2 Posology and method of administration / Patients with hepatic impairment).

The extent as well as the duration of interactions should be taken into account when administering nimodipine together with the following drugs:

Rifampicin –

Ffrom experience with other calcium antagonists it has to be expected that rifampicin accelerates the metabolism of Nimotop tablets nimodipine due to enzyme induction. Thus efficacy of Nimotop tablets nimodipine could be significantly reduced when concomitantly administered with rifampicin. The use of nimodipine in combination with rifampicin is, therefore, contraindicated. (See section 4.3 contraindications).

Cytochrome P450 3A4 system-inducing antiepileptic drugs such as, phenobarbital, phenytoin or carbamazepine: –

Pprevious chronic administration of these drugs markedly reduces the bioavailability of orally administered nimodipine. Therefore, the concomitant use of oral nimodipine and these antiepileptic drugs is contraindicated. (See section 4.3 contraindications).

Upon co-administration with the following inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, an adaption in the nimodipine dose should be considered (see section 4.2 Posology and method of administration):

Macrolide antibiotics (e.g. erythromycin) –

Nno interaction studies have been carried out between nimodipine and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit the cytochrome P450 3A4 system and the potential for drug interaction cannot be ruled out at this stage. Therefore, macrolide antibiotics should not be used in combination with nimodipine (see section 4.4 Special warnings and precautions for use). Azithromycin, although structurally related to the class of macrolide antibiotics, is void of CYP3A4 inhibition.

Anti-HIV protease inhibitors (e.g. ritonavir) –

Nno formal studies have been performed to investigate the potential interaction between nimodipine and anti-HIV protease inhibitors. Drugs of this class have been reported to be potent inhibitors of the cytochrome P450 3A4 system. Therefore, the potential for a marked and clinically relevant increase in nimodipine plasma concentrations upon co-administration with these protease inhibitors cannot be excluded. (See section 4.4 Special warnings and precautions for use).

Azole anti-mycotics (e.g. ketoconazole) –

Aa formal interaction study investigating the potential interaction between nimodipine and ketoconazole has not been performed. Azole anti-mycotics are known to inhibit the cytochrome P450 3A4 system and various interactions have been reported for other dihydropyridine calcium antagonists. Therefore, when administered together with oral nimodipine, a substantial increase in systemic bioavailability of nimodipine due to a decreased first pass metabolism cannot be excluded. (See section 4.4 Special warnings and precautions for use).

Nefazodone –

Nno formal studies have been performed to investigate the potential interaction between nimodipine and nefazodone. This antidepressant drug has been reported to be a potent inhibitor of the cytochrome P450 3A4 system. Therefore, the potential for an increase in nimodipine plasma concentrations upon co-administration with nefazodone cannot be excluded. (See section 4.4 Special warnings and precautions for use).

Fluoxetine –

Cconcomitant administration of nimodipine with the antidepressant fluoxetine, once steady state has been achieved has led to approximately 50% higher plasma nimodipine levels.  Fluoxetine plasma levels were exposure was markedly decreased, however the while its active metabolite, norfluoxetine was not affected (See section 4.4 Special warnings and precautions for use).

Quinupristin/dalfopristin

Based on experience with the calcium-antagonist, nifedipine, co-administration of quinupristin/dalfopristin may lead to increased plasma concentrations of nimodipine (See section 4.4 Special warnings and precautions for use).

The steady-state concomitant administration of nimodipine and nortriptyline led to a slight decrease in nimodipine plasma concentrations with unaffected nortriptyline plasma concentrations.

Cimetidine

The simultaneous administration of nimodipine with the anticonvulsant valproic acid or the H2-antagonist cimetidine can lead to an increase in the plasma nimodipine concentration of nimodipine (See section 4.4 Special warnings and precautions for use).

Valproic acid

The simultaneous administration of the anticonvulsant Valproic acid can lead to an increase in the plasma nimodipine concentration (See section 4.4 Special warnings and precautions for use).

Further drug interaction:

Nortriptyline

The steady-state concomitant administration of nimodipine and nortriptyline led to a slight decrease in nimodipine exposure with unaffected nortriptyline plasma concentrations.

Based on experience with the calcium-antagonist, nifedipine, co-administration of quinupristin/dalfopristin may lead to increased plasma concentrations of nimodipine.

Effects of nimodipine on other drugs

Blood pressure lowering drugs:

Nimodipine may increase the blood pressure lowering effect of concomitant antihypertensives, such as

·                                               diuretics

·                                               beta-blockers

·                                               ACE inhibitors

·                                               A1-antagonists

·                                               other calcium antagonists

·                                               alpha-adrenergic blocking agents

·                                               PDE5 inhibitors

·                                               alpha-methyldopa

However, iIf a combination of this type proves unavoidable particularly careful monitoring of the patient is necessary.

Zidovudine

In a monkey study simultaneous administration of anti-HIV drug zidovudine i.v. and nimodipine bolus i.v. resulted for zidovudine in significantly higher AUC, whereas the distribution volume and clearance were significantly reduced. Animal studies have shown that when nimodipine and zidovudine are administered concomitantly, the AUC for zidovudine was increased, and the volume of distribution and clearance rate decreased.  The clinical relevance of this interaction is unknown, but since the side-effect profile of zidovudine is known to be dose-related, this interaction should be considered in patients receiving nimodipine and zidovudine concomitantly.

Drug-food interactions:

Grapefruit juice

Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of dyhydropyridine calcium antagonists together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nimodipine due to a decreased first pass metabolism or reduced clearance.

Other types of interaction

The intake of grapefruit juice is not recommended in combination with nimodipine as it can result in increased plasma nimodipine concentrations due to the inhibition of the oxidative metabolism of dihydropyridines. As a consequence, the blood pressure lowering effect may be increased. After intake of grapefruit juice this This effect may last for at least 4 days after the last ingestion of grapefruit juice.

Ingestion of grapefruit / grapefruit juice is therefore to be avoided while taking

nimodipine (see Section 4.2 Posology and method for administration).

Interactions shown not to exist

There is no evidence of a potential interaction between nimodipine and haloperidol.

Concomitant administration of oral nimodipine and diazepam, digoxin, glibenclamide, indometacin, ranitidine and warfarin did not reveal any potential for mutual interaction.

Section 4.6: Fertility, Pregnancy and lactation

Pregnancy:

There are no adequate and well controlled studies in pregnant women. The safety of this medicinal product for use in human pregnancy has not been established. An evaluation of experimental animal studies following oral administration does not indicate direct or indirect harmful effects with regard to reproduction, development of the embryo or foetus, the course of gestation, and peri- and post-natal development. If nimodipine is to be administered during pregnancy, the benefits and potential risks must be carefully weighed according to the severity of the clinical picture.

Lactation:

Nimodipine and its metabolites have been shown to appear in human milk at concentrations of the same order of magnitude as corresponding maternal plasma concentrations. Nursing mothers are advised not to breast-feed when taking this drug.

In-vitro fertilisation Fertility:

In single cases of in-vitro fertilisation calcium antagonists have been associated with reversible biochemical changes in the spermatozoa’s head section that may result in impaired sperm function. The relevance of this finding in short-term treatment is unknown

Section 4.8: Undesirable effects

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).

Adverse drug reactions (ADRs) 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) are listed below:

            Table 01: ADR table aSAH

Section 4.9: Overdose

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.

In the event of acute overdosage, treatment with Nimotop nimodipine must be discontinued immediately. Emergency measures should be governed by the symptoms. 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 Since no specific antidote is known, subsequent treatment for other side effects should be aimed at governed by the most prominent symptoms.

Section 10: Date of revision of the text

June 2010 April 2013

Note: New text highlighted in red.

1.         NAME OF THE MEDICINAL PRODUCT

            Change from “Nimotop 30 mg Tablets” to “Nimotop 30 mg Film-coated Tablets.”

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

            Each tablet contains 30 mg nimodipine.

            For a full list of excipients, see section 6.1.

3.         PHARMACEUTICAL FORM

            Film-coated tablet (Tablet).      

Yellow, film-coated tablet, about 10 mm in diameter, marked with the Bayer cross on one face and with “SK” on the reverse.

6.         PHARMACEUTICAL PARTICULARS

6.1       List of excipients

Change to formatting layout of this section.

6.5       Nature and contents of container

            PP/aluminium blister packs, contained in cardboard outer, containing 100 x 30mg tablets.

Not all pack sizes or types may be marketed.

9.         DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

            Date of first authorisation:          15 February 1994

Date of last renewal:     15 February 2009

10.       DATE OF REVISION OF THE TEXT

June 2010

Sections 4.2, 5.1, 5.2, 5.3 and 6.6 where updated following internal review.