Consumer medicine information

Nimodipine Juno

Nimodipine

BRAND INFORMATION

Brand name

Nimodipine Juno

Active ingredient

Nimodipine

Schedule

SUMMARY CMI

NIMODIPINE JUNO

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using NIMODIPINE JUNO?

NIMODIPINE JUNO contains the active ingredient nimodipine. NIMODIPINE JUNO is used to prevent or to treat a lack of blood supply in the brain caused by narrowing of the blood vessels after a haemorrhage (burst blood vessel in the brain).

For more information, see Section 1. Why am I using NIMODIPINE JUNO? in the full CMI.

2. What should I know before I use NIMODIPINE JUNO?

Do not use if you have ever had an allergic reaction to NIMODIPINE JUNO or any of the ingredients listed at the end of the CMI.

NIMODPINE JUNO contains alcohol. Tell your doctor if you suffer from alcoholism or impaired alcohol metabolism.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use NIMODIPINE JUNO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with NIMODIPINE JUNO and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use NIMODIPINE JUNO?

Your doctor will decide the appropriate dose for you.
A doctor or nurse will prepare and administer the infusion.
Follow all instructions given to you by your doctor and pharmacist.

More instructions can be found in Section 4. How do I use NIMODIPINE JUNO? in the full CMI.

5. What should I know while using NIMODIPINE JUNO?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using NIMODIPINE JUNO. Keep all of your doctor's appointments so that your progress can be checked.
Things you should not do	Do not stop using this medicine suddenly unless your doctor tells you to.
Driving or using machines	NIMODIPINE JUNO contains alcohol. Your ability to drive or operate heavy machinery may be impaired.
Drinking alcohol	NIMODIPINE JUNO contains alcohol. Avoid alcohol. Alcohol may make you feel more sleepy and could increase the risk of serious side effects such as dizziness or faintness.
Looking after your medicine	NIMODIPINE JUNO should be stored below 25°C and protected from light. NIMODIPINE JUNO should not be allowed to come into contact with polyvinyl chloride (PVC). Keep it where young children cannot reach it.

For more information, see Section 5. What should I know while using NIMODIPINE JUNO? in the full CMI.

6. Are there any side effects?

NIMODIPINE JUNO may cause allergic reactions, irregular heartbeats or lack of bowel movements.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

NIMODIPINE JUNO

Active ingredient(s): nimodipine

Consumer Medicine Information (CMI)

This leaflet provides important information about using NIMODIPINE JUNO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using NIMODIPINE JUNO.

Where to find information in this leaflet:

1. Why am I using NIMODIPINE JUNO?
2. What should I know before I use NIMODIPINE JUNO?
3. What if I am taking other medicines?
4. How do I use NIMODIPINE JUNO?
5. What should I know while using NIMODIPINE JUNO?
6. Are there any side effects?
7. Product details

1. Why am I using NIMODIPINE JUNO?

NIMODIPINE JUNO contains the active ingredient nimodipine. NIMODIPINE JUNO belongs to a group of drugs called calcium channel blockers. NIMODIPINE JUNO works by relaxing the smooth muscle of the small blood vessels in the brain.

This allows narrowed vessels to open up, thereby increasing blood flow, reducing blood pressure, and improving circulation.

NIMODIPINE JUNO is used to prevent or to treat a lack of blood supply in the brain caused by narrowing of the blood vessels after a haemorrhage (burst blood vessel in the brain).

2. What should I know before I use NIMODIPINE JUNO?

Warnings

Do not use NIMODIPINE JUNO if:

you are allergic to nimodipine, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
Oral nimodipine (other brands) if you are taking:
- phenobarbitone, phenytoin, carbamazepine or other anticonvulsants; medicines used to treat epilepsy or seizures
- rifampicin, an antibiotic used to treat tuberculosis and other serious infections

Check with your doctor if you:

have any other medical conditions:
- low blood pressure
- heart conditions
- fluid retention in the brain
- kidney or liver disease
- bowel obstruction
- take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Alcohol

Tell your doctor if you suffer from alcoholism or impaired alcohol metabolism. Patients with liver disease, epilepsy, pregnant or breastfeeding should take into account that NIMODIPINE JUNO contains alcohol.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with NIMODIPINE JUNO and affect how it works. These include:

medicines used to lower your blood pressure and/or reduce water retention, such as frusemide
medicines used to treat tuberculosis, such as
rifampicin
medicines used to treat epilepsy or seizures, such as carbamazepine, phenobarbitone, phenytoin, sodium valproate
certain antibiotics, such as erythromycin, quinupristin/dalfopristin, aminoglycosides, cephalosporins
medicines used to treat HIV infection and AIDS, such as ritonavir, zidovudine
antifungals, such as ketoconazole
medicines used to treat depression, such as
nefazodone, fluoxetine, nortryptyline
medicines used to treat heartburn, such as cimetidine
medicines used to treat cancer, such as doxorubicin, vincristine

Food that may increase the effect of NIMODIPINE JUNO include:

You should not eat grapefruit or drink grapefruit juice while you are on NIMODIPINE JUNO because this can increase the effects of it.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect NIMODIPINE JUNO.

4. How do I use NIMODIPINE JUNO?

How much to use

Your doctor will decide the appropriate dose for you.

When to use NIMODIPINE JUNO

NIMODIPINE JUNO should be used as directed by your doctor.

If you forget to use NIMODIPINE JUNO

NIMODIPINE JUNO is administered by a doctor or nurse in a hospital. If you miss your dose at the usual time, tell your doctor.

Do not take a double dose to make up for the dose you missed.

If you use too much NIMODIPINE JUNO

As NIMODIPINE JUNO is given to you in hospital under the supervision of your doctor, it is very unlikely that you will receive an overdose. Symptoms of a nimodipine overdose include the effects listed below in the ‘Side Effects’ section but are usually of a more severe nature.

5. What should I know while using NIMODIPINE JUNO?

Things you should do

Remind any doctor, dentist or pharmacist you visit that you have been given nimodipine.

Things you should not do

Do not stop using this medicine suddenly without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how NIMODIPINE JUNO affects you.

NIMODIPINE JUNO may cause dizziness or faintness in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may cause dizziness or faintness to be worse..

Looking after your medicine

NIMODIPINE JUNO will be stored in the pharmacy or on the ward. The injection is kept in a cool dry place, protected from light, where the temperature stays below 25°C.

Getting rid of any unwanted medicine

Any unwanted medicine will be disposed of in a safe manner by your doctor, nurse or pharmacist.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effects	What to do
signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue, or other parts of the body, shortness of breath, wheezing, or trouble breathing irregular heartbeats lack of bowel movement, stomach pain or cramping	Stop taking nimodipine. Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What NIMODIPINE JUNO contains

Active ingredient (main ingredient)	Nimodipine
Other ingredients (inactive ingredients)	Ethanol Macrogol 400 Sodium citrate dihydrate Citric acid Water for injections
Potential allergens	Ethanol. This medicine does not contain lactose, sucrose, gluten, tartrazine or other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What NIMODIPINE JUNO looks like

NIMODIPINE JUNO is a clear slightly yellowish solution containing 10 mg nimodipine/50 mL contained in a glass vial with a grey rubber closure and sealed with a flip off top packed in packs of 5. (Aust R 335255).

Who distributes NIMODIPINE JUNO

Juno Pharmaceuticals Pty Ltd
42 Kelso Street,
Cremorne,
VIC 3121

Pharmacovigilance & Medical Enquiries
Phone: 1800 620 076
Email: [email protected]

This leaflet was prepared in August 2021.

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Nimodipine Juno

Active ingredient

Nimodipine

Schedule

1 Name of Medicine

Nimodipine.

2 Qualitative and Quantitative Composition

Nimodipine is a yellow crystalline substance, practically insoluble in water.
Nimodipine is light sensitive but to a much lesser degree than nifedipine.
Nimodipine Juno is available as a 0.2 mg/mL concentrated intravenous infusion solution.

Excipients with known effect.

Ethanol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nimodipine Juno concentrated intravenous infusion solution is presented as a clear slightly yellowish solution containing 10 mg nimodipine/50 mL and 10 g alcohol/50 mL in a glass vial.

4 Clinical Particulars

4.1 Therapeutic Indications

Prophylaxis and treatment of ischaemic neurological deficits caused by cerebral vasospasm after subarachnoid haemorrhage following ruptured intracranial aneurysm, in patients who are in good neurological condition post-ictus, e.g. Hunt and Hess Grades I-III (see Section 5 Pharmacological Properties).

4.2 Dose and Method of Administration

Nimodipine tablet is unavailable in this brand however is available in other brands. Where correct dosing requires nimodipine tablet formulation, refer to the specific product information for this formulation for its complete dosage and administration instructions.

Dosage: Nimodipine Juno concentrated intravenous infusion solution.

For single use in one patient only. Discard any residue.

Continuous intravenous infusion.

Nimodipine Juno concentrated intravenous infusion solution must be administered by co-infusion via a three-way stopcock to the central catheter. The initial dosage is 5 mL Nimodipine Juno concentrated intravenous solution (= 1 mg nimodipine) per hour infused continuously for the first 2 hours (approximately 15 microgram/kg body weight/hr). Co-infusion solution must be administered at a rate of 20 mL per hour with this initial dosage. If this dosage is tolerated, particularly if there is no severe reduction in blood pressure, the dosage should then be increased to 10 mL Nimodipine Juno concentrated intravenous infusion solution per hour (= 2 mg nimodipine/h) (approximately 30 microgram/kg body weight/hr) with a corresponding increase in the rate of co-infusion solution to 40 mL per hour.
Patients whose body weights are distinctly below 70 kg or who have labile blood pressure can start with a dose of 2.5 mL Nimodipine Juno concentrated intravenous infusion solution/hr (= 0.5 mg nimodipine/h) with corresponding reduction in the rate of co-infusion and, if at all possible, the dosage should not be raised above 5 mL nimodipine concentrated intravenous infusion solution per hour. The treatment should be discontinued if necessary.

Intracisternal instillation.

Intracisternal instillation has been employed in uncontrolled trials in combination with IV/oral administration. A 1:19 ratio for dilution with Ringer's was tested in vitro with a very small risk of crystallisation. The dilute solution of nimodipine was used immediately after preparation. If the dilute solution is not used immediately, it should be discarded.
Patients with hepatic insufficiency may have substantially reduced clearance and approximately doubled plasma concentration; dosage should be reduced to 2.5 mL Nimodipine Juno concentrated intravenous infusion solution per hour and/or one nimodipine tablet (30 mg, available in other brands) every 4 hours in these patients.
In cases of severely disturbed kidney or liver function, particularly in cirrhosis of the liver, the effects and side effects, e.g. 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.

Administration: Nimodipine Juno concentrated intravenous infusion solution.

Nimodipine Juno concentrated intravenous infusion solution is administered as a continuous intravenous infusion via a central catheter using an infusion pump. A three-way stopcock should be used to connect the Nimodipine Juno polyethylene tube with the co-infusion line and the central catheter.
Only infusion pumps with polyethylene (PE) infusion tubing, polypropylene (PP) syringes and polyethylene or polypropylene extensions, taps, connectors may be used. Do not use polyvinylchloride (PVC) infusion tubing as nimodipine is adsorbed by the tubing.
Polyethylene or polyurethane catheters are to be used, only in conjunction with a polycarbonate stop-cock.
PVC Y-connector tubing must not be used and the rates of administration of recommended co-infusion solutions must be followed due to the possibility of crystal formation as seen in in vitro tests with Nimodipine Juno concentrated intravenous infusion solution at higher dilutions.
All infusion tubings must be changed every 24 hours.
Nimodipine Juno concentrated intravenous infusion solution should be co-infused with approximately 40 mL/h of any of the following infusion solutions which are compatible at the recommended 1 to 4 mixing ratio:
Sodium chloride intravenous infusion 0.9%, glucose intravenous infusion 5% (Glucose 5%), compound sodium lactate intravenous infusion solution (Hartmann's solution for injection/lactated Ringer's solution), lactated Ringer's solution with magnesium, Dextran 40, Mannitol (10%), hetastarch 6% (Poly (0-2-hydroxyethyl) starch 6%), Human albumin 5% or blood.
Nimodipine Juno concentrated intravenous infusion solution must not be mixed with any other drugs and must not be added to an infusion bag or bottle. Infusion solutions other than those recommended above should not be used. Nimodipine Juno concentrated intravenous infusion solution has a pH of 6.0-7.5.
Parenteral drug products should be inspected visually for particulate matter and colour change prior to administration. Any residual solution should not be kept for later use.
Nimodipine concentrated intravenous infusion solution is slightly light-sensitive. Its use in direct sunlight should be avoided. No special protective measures need be taken for up to 10 hours if Nimodipine Juno concentrated intravenous infusion solution is being administered in diffuse daylight or in artificial light.
Administration of Nimodipine Juno concentrated intravenous infusion solution should be continued during anaesthesia, surgery, and angiography.

Duration of administration.

Prophylaxis and treatment of ischaemic symptoms caused by vasospasm after subarachnoid haemorrhage should commence as soon as possible or within 4 days of the diagnosis of SAH and continue for at least 7 days up to a maximum of 14 days.
If during prophylactic administration of nimodipine, the source of the haemorrhage is treated surgically, intravenous treatment with nimodipine should be continued post-operatively for at least 5 days.
After the end of the infusion therapy, it is advisable to continue with oral administration (available in other brands).

4.3 Contraindications

Nimodipine tablet is unavailable in this brand, however this dosage form is available in other brands. Contraindications, Special warnings and precautions for use, Interactions with other medicines and other forms of interactions, Fertility, pregnancy and lactation and Pharmacological properties information obtained using nimodipine tablet formulation is also included in the following sub-sections for prescriber information.
Nimodipine Juno concentrated intravenous infusion solution must not be used in cases of hypersensitivity to nimodipine or any of the excipients.
The use of nimodipine tablets (available in other brands) in combination with rifampicin is contraindicated as efficacy of nimodipine tablets may be significantly reduced when concomitantly administered with rifampicin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The concomitant use of oral nimodipine (available in other brands) and the antiepileptic drugs phenobarbital, phenytoin or carbamazepine is contraindicated as efficacy of nimodipine tablets may be significantly reduced (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Blood pressure.

Nimodipine has the haemodynamic effects expected of a calcium channel blocker although they are generally not marked at usual therapeutic doses. Blood pressure should be carefully monitored during treatment with nimodipine as a decrease in blood pressure has been reported in about 5% to 7% of SAH patients receiving oral nimodipine. Caution is required in patients with hypotension (systolic pressure lower than 100 mm Hg). The use of nimodipine is not generally recommended in patients taking antihypertensive drugs, including other calcium channel blockers, since it may potentiate the effects of these medications.
Simultaneous intravenous administration of β-blockers can lead to the mutual potentiation of negative inotropic effects and even to decompensated heart failure.
Please refer also to the section on Use in renal impairment.
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 ischaemia) versus the benefit (e.g. improvement of brain perfusion).

Cerebral oedema or severely raised intracranial pressure.

Although treatment with nimodipine has not been shown to be associated with increases in intracranial pressure, cautious use and close monitoring is recommended in these cases when the water content of the brain tissue is elevated (generalised cerebral oedema).

Use in renal impairment.

There are insufficient data on patients with impaired renal function. However, patients with severe renal insufficiency should be carefully monitored with respect to any lowering of blood pressure when receiving nimodipine treatment.
Renal function should be closely monitored during intravenous nimodipine treatment in patients with known renal disease and/or receiving nephrotoxic drugs simultaneously (e.g. aminoglycosides, cephalosporins, frusemide). If deterioration is found discontinuation of the treatment should be considered.

Use in hepatic impairment.

The metabolism of nimodipine is decreased in patients with impaired hepatic function. Such patients should have their blood pressure and pulse rate monitored closely and should be given a lower dose (see Section 4.2 Dose and Method of Administration).
Elevations in one or more liver function test result, including elevated serum concentrations of LDH, alkaline phosphatase, or ALT (SGPT), have been reported in less than 1% of patients with SAH receiving oral nimodipine. Reversible increases in creatinine kinase (CK), creatinine phosphokinase (CPK), AST (SGOT), ALT (SGPT), gamma glutamyl transferase (GGT), gamma-glutamyltranspeptidase (GGTP), bilirubin and amylase also have been reported in patients receiving nimodipine, principally during intravenous administration of the drug. It has been suggested that such increases in liver function test results were caused by alcohol in the intravenous formulation rather than by the drug itself; however, in at least 2 studies, alcohol could not be detected in the blood of patients receiving an alcohol-containing nimodipine injection, and elevated transaminase concentrations also have been reported following oral administration of the drug in clinical studies.
Adverse hepatic effects reported in less than 1% of patients with SAH receiving oral nimodipine include hepatitis and jaundice.

Intestinal pseudo-obstruction and ileus.

Intestinal pseudo-obstruction (paralytic ileus) has been reported rarely. A causal relationship to nimodipine cannot be ruled out. In three cases, the condition responded to conservative management, but a fourth patient required surgical decompression of the extremely distended colon.

Alcohol content.

When treatment with Nimodipine Juno concentrated intravenous infusion solution is administered during pregnancy, the benefits and the potential risks must be carefully assessed according to the severity of the clinical situation.
Nimodipine Juno concentrated intravenous infusion solution contains 23.7% 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 product may alter the effects of other medicines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Drugs altering the cytochrome P450 3A4 system.

Nimodipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nimodipine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
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, blood pressure should be monitored and, if necessary, a reduction of the nimodipine dose should be considered.

Dermatologic effects.

Rash, requiring discontinuance of the drug in at least one case, and acne have been reported in less than 1% of patients with SAH receiving oral nimodipine. Pruritus, diaphoresis, and haematoma also have been reported in less than 1% of such patients.

Use in the elderly.

No data available.

Paediatric use.

Safety and effectiveness in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Hypotensive agents.

In patients with elevated blood pressure who are receiving antihypertensive drugs, Nimodipine Juno can potentiate the blood-pressure-lowering effect of the concomitant medication. Blood pressure should be carefully monitored.

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 to induce this enzyme system may therefore alter the first pass or the clearance of nimodipine.
The extent as well the duration of interactions should be taken into account when administering nimodipine together with the following drugs:

Rifampicin.

Rifampicin is expected to increase the rate of metabolism of Nimodipine Juno tablets due to enzyme induction, as experienced with other calcium antagonists such as nifedipine. Thus, the efficacy of Nimodipine Juno tablets may be significantly reduced when concomitantly administered with rifampicin. The use of nimodipine in combination with rifampicin is therefore contraindicated (see Section 4.3 Contraindications).

Anticonvulsants.

Few data are available on the interaction of nimodipine and anticonvulsant drugs. However, a study of epileptic patients receiving long-term treatment with the anticonvulsants carbamazepine, phenobarbitone or phenytoin, either alone or in combination, showed that plasma concentrations of nimodipine given as a single oral dose of 60 mg were markedly reduced (approx. 7 fold decrease in AUC and 8-10 fold in C_max). This was due to the well-known enzyme inducing properties of these antiepileptic drugs, leading to a reduced oral bioavailability of nimodipine by enhanced first pass metabolism. This phenomenon has been reported for many high clearance drugs like nimodipine and also for other dihydropyridine calcium antagonists.
Thus, the concomitant administration of anticonvulsants and oral nimodipine is contraindicated in epileptic patients or patients on long-term/chronic anticonvulsant therapy, because the nimodipine serum concentration may be considerably lowered due to the induction of drug-metabolising enzymes (see Section 4.3 Contraindications).
A general guide concerning dose adjustments of nimodipine tablets is not possible because the extent of enzyme induction and changed capacity for nimodipine first pass metabolism may show large inter-individual differences.
Conversely, nimodipine plasma concentrations following administration of 60 mg single oral dose were increased (approx. 50%) in epileptic patients on long-term sodium valproate therapy. These patients may require smaller doses. The simultaneous administration of valproic acid can lead to an increase in the plasma nimodipine concentration (see Section 4.4 Special Warnings and Precautions for Use).

Effect of nimodipine on anticonvulsant therapy.

No effect was observed on the steady state plasma concentrations of the abovementioned anticonvulsants following the administration of a single oral 60 mg dose of nimodipine. Multiple dosing has not been investigated, but no effect of nimodipine on the bioavailability of these drugs is expected.
Upon co-administration with the following inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, an adaptation in the nimodipine dose should be considered (see Section 4.2 Dose and Method of Administration).

Macrolide antibiotics (e.g. erythromycin).

No 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 antibiotic, does not inhibit CYP3A4.

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

No 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).

A formal interaction study investigating the potential of drug 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.

No 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. 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.

The steady-state concomitant administration of nimodipine with the antidepressant fluoxetine led to about 50% higher nimodipine plasma concentrations. Fluoxetine exposure was markedly decreased, while its active metabolite norfluoxetine was not affected.

Nortryptyline.

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

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).

Cimetidine.

A study in eight healthy volunteers has shown a 50% increase in mean peak nimodipine plasma concentrations and a 90% increase in the mean area under the curve, after a one-week course of cimetidine at 1,000 mg/day and nimodipine at 90 mg/day. This effect may be mediated by the known inhibition of hepatic cytochrome P-450 by cimetidine, which could decrease first-pass metabolism of nimodipine (see Section 4.4 Special Warnings and Precautions for Use).

Antineoplastic agents.

There is in vitro evidence that calcium-channel blocking agents, including nimodipine can enhance the cytotoxic effects of certain antineoplastic agents, e.g. doxorubicin, vincristine, but the clinical importance of these findings remains to be established.

Effects of nimodipine on other drugs.

Hypotensive agents.

Nimodipine may increase the blood pressure lowering effect of concomitantly applied antihypertensives, such as: diuretics, β-blockers, ACE inhibitors, A1-antagonists, other calcium antagonists, α-adrenergic blocking agents, PDE5 inhibitors, α-methyldopa.
However, if a combination of this type proves unavoidable particularly careful monitoring of the patient is necessary.

Zidovudine.

In a monkey study, simultaneous administration of zidovudine i.v. and nimodipine bolus i.v. resulted in a significantly higher AUC and significantly reduced distribution volume and clearance for zidovudine.

Other forms of interaction.

Because nimodipine concentrated intravenous infusion solution contains 23.7% (v/v) of ethanol, interactions with alcohol-incompatible medicines should be taken into consideration (see Section 4.4 Special Warnings and Precautions for Use).
Renal function can deteriorate if potentially nephrotoxic drugs are given simultaneously with Nimodipine Juno (see Section 4.4 Special Warnings and Precautions for Use).

Drug-food interaction.

Grapefruit juice.

Grapefruit juice inhibits the oxidative metabolism of dihydropyridines. Concomitant intake of grapefruit juice and nimodipine can result in increased plasma concentrations and prolonged action of nimodipine due to a decreased first pass metabolism or reduced clearance.
As a consequence, the blood pressure lowering effect may be increased. After intake of grapefruit juice 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility were observed in male and female rats treated orally with nimodipine at 30 mg/kg/day (0.8 times the maximum recommended human dose on a mg/m² body surface area basis). In single cases of in vitro fertilisation calcium channel blockers have been associated with reversible biochemical changes in the spermatozoa's head section that may result in impaired sperm function.
(Category C)
Animal studies have shown no consistent evidence of teratogenic activity in rats or rabbits at oral doses up to 100 mg and 30 mg/kg/day respectively (2.5- and 1.5-times the maximum recommended human dose on a mg/m² body surface area basis), or at intravenous doses up to 0.5 mg/kg/day in both species (estimated relative exposure, 0.1-0.2). Nimodipine was embryotoxic in rats, causing reduced fetal weight from 30 mg/kg/day and resorption at 100 mg/kg/day when administered orally during organogenesis (estimated relative exposure, 0.8 and 2.5, respectively). No embryotoxicity occurred in rabbits at oral doses up to 10 mg/kg/day (estimated relative exposure, 0.5). Peri/postnatal studies in rats showed that oral doses of 30 mg/kg/day were associated with marginally higher incidences of skeletal variation, stunted fetuses and stillbirths. Nimodipine carries the potential to produce fetal hypoxia associated with maternal hypotension.
There are no adequate and well controlled studies in pregnant women to assess directly the effect on human fetuses. Nimodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nimodipine and its metabolites have been shown to appear in breast milk at concentrations of the same order of magnitude as corresponding maternal plasma concentrations. Nursing mothers are advised not to breast feed their babies when taking the drug.

4.7 Effects on Ability to Drive and Use Machines

In principle the ability to drive and use machines can be impaired in connection with the possible occurrence of dizziness.

4.8 Adverse Effects (Undesirable Effects)

Adverse drug reactions (ADRs) based on clinical trials with nimodipine in the indication SAH sorted by CIOMS III categories of frequency (placebo-controlled studies: nimodipine N=703; placebo= 692; uncontrolled studies: nimodipine N=2496; status 31 Aug 2005) are listed below.
The frequencies of ADRs reported with nimodipine are summarised in Table 1. Within each frequency grouping, adverse effects are presented in order of decreasing seriousness. Frequencies are defined as: uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000).

Post marketing adverse events.

Events described in MedDRA preferred terms:

Investigations/ vascular disorders.

hypotension.

Nervous system disorders.

headache.

Gastrointestinal.

nausea and vomiting.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Symptoms of acute overdosage to be anticipated are flushing, headache, marked lowering of the blood pressure, tachycardia or bradycardia, and (after oral administration) gastrointestinal complaints and nausea.

Treatment of overdosage.

In the event of acute overdosage, treatment with Nimodipine Juno must be discontinued immediately. Active cardiovascular support should include close monitoring of cardiac and respiratory function. Intravenous dopamine or noradrenaline may be helpful in restoring blood pressure. Since no specific antidote is known, subsequent treatment for other side effects should be governed by the most prominent symptoms. Since Nimodipine Juno is highly protein bound, dialysis is not likely to be of benefit.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nimodipine belongs to the class of pharmacological agents known as calcium channel blockers. Nimodipine is a calcium channel blocking agent belonging to the 1,4dihydropyridine group. The mechanism(s) of nimodipine's clinical benefit in patients with subarachnoid haemorrhage has not been fully elucidated. Current evidence suggests that it may have a preferential cerebral vasodilator action and/or a direct effect involving prevention of calcium overload in neurons. It dilates the small resistance cerebral vessels and increases the cerebral blood flow, the increased perfusion being generally more pronounced in brain regions with preliminary damage and restricted circulation than in healthy regions. The improvement in cerebral circulation is particularly evident in patients with cerebral vasospasm after subarachnoid haemorrhage, particularly in Hunt and Hess grades I-III patients (see Table 2). Nimodipine produces significant reductions in ischaemic neurological deficits caused by vasospasm and in mortality.

The contractile processes of the cerebral arterial smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarisation as slow ionic transmembrane currents. Nimodipine binds to specific receptor sites in the central nervous system. It inhibits calcium ion transfer into these cells and inhibits contractions of vascular smooth muscle.

Clinical trials.

In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body. It is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations of nimodipine as high as 12.5 nanogram/mL have been detected in the cerebrospinal fluid of nimodipine treated subarachnoid haemorrhage (SAH) patients.
Based on animal experiments, it was hoped that nimodipine would prevent cerebral arterial spasm in SAH patients. While clinical studies demonstrated a favourable effect by nimodipine on the severity of neurological deficits caused by cerebral vasospasm following SAH, there is no arteriographic evidence that the drug either prevents or relieves the spasm of these arteries. The actual mechanism of action in humans is, therefore, unknown.

5.2 Pharmacokinetic Properties

Absorption.

The orally administered active substance nimodipine is almost completely absorbed. The unchanged active substance and its early "first pass" metabolites are detected in plasma as little as 10-15 minutes after the ingestion of the tablet. Following multiple-dose oral administration (3 x 30 mg/day), the mean peak plasma concentrations (C_max) are 7.3-43.2 nanogram/mL in elderly individuals, these being reached after 0.6-1.6 h (t_max). 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/h, mean steady-state plasma concentrations of 17.6-26.6 nanogram/mL are achieved. After intravenous bolus injections, the plasma nimodipine concentrations fall biphasically with half-lives of 5-10 minutes and about 60 minutes. The distribution volume (Vss, 2-compartment model) for intravenous administration is calculated to be 0.9-1.6 L/kg body weight. The total (systemic) clearance is 0.6-1.9 L/h/kg. (See Figure 1.)

Nimodipine undergoes extensive first pass metabolism in the liver. The mean bioavailability of nimodipine tablets ranges from ± 3-12% in healthy individuals to 16% (range 3-30%) in patients with SAH.
Bioavailability is significantly increased in patients with hepatic disease (e.g. cirrhosis) with C_max approximately double that in normal patients which necessitates lowering the dose in this group of patients (see Section 4.2 Dose and Method of Administration).
The effects of a standard breakfast on the bioavailability of nimodipine tablets were investigated in two separate studies. From the results it was concluded that, although the rate of absorption is delayed as evidenced by the decrease in C_max (of approx. 40%) and the increase of t_max (approx. 100%), the presence of food does not alter the extent of absorption of nimodipine tablets.

Distribution.

Studies in animals indicate that nimodipine is widely distributed into body tissues after oral or intravenous administration. Following intravenous administration in healthy individuals, nimodipine distributes rapidly into the central compartment with a half-life of approximately 67 minutes; the volume of distribution of the central compartment averaged 0.43 L/kg. The steady-state volume of distribution following intravenous administration has been reported to range from 0.94-2.3 L/kg. Plasma protein binding of unchanged nimodipine averages more than 95% and is independent of concentration over a range of 10 nanogram/mL to 10 microgram/mL.
Nimodipine appears to distribute to a limited extent into CSF. During intravenous infusion of nimodipine at a rate of 2 mg/hour for up to 14 days in patients with SAH, mean CSF and plasma concentrations of nimodipine averaged approximately 0.3 and 77 nanogram/mL, respectively. After oral administration of nimodipine 0.35 mg/kg every 4 hours for 3 weeks, mean CSF and plasma nimodipine concentrations were 0.77 and 6.9 nanogram/mL, respectively. However, concentrations as high as 12.5 nanogram/mL reportedly have been detected.
Nimodipine and/or its metabolites have been shown to appear in rat milk at concentrations much higher than in maternal plasma. Nimodipine itself has been shown to appear in human breast milk; the concentrations were lower than in maternal plasma.

Excretion.

Nimodipine concentrations appear to decline in a biphasic manner. The half-life (T½) was 1.21.8 hours after intravenous infusion; after oral administration, the elimination T½ was 5-10 hours and dose-independent. The elimination T½ from plasma of total radioactivity was 14 hours with ³H nimodipine.
No sign of accumulation was noted in patients receiving 40 mg nimodipine three times daily for 7 days.
Nimodipine is extensively metabolised in the liver via the cytochrome P450 3A4 system, with approximately 10%, or less than 1%, of an orally administered dose present in plasma or urine, respectively, as unchanged drug (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). All metabolites of nimodipine are either inactive or substantially less active than the parent drug.
Cumulative excretion of metabolites in urine is approximately 50% of the dose after 48 hours and 30% in faeces.
Plasma clearance of nimodipine varies considerably, averaging 0.84 L/kg per hour (range: 0.51-1.15 L/kg per hour) in healthy individuals and 1.18 L/kg per hour (range: 0.57-1.77 L/kg per hour) in patients with SAH. Clearance of nimodipine may be decreased substantially in patients with hepatic dysfunction.
Patients with renal impairment showed a substantial prolongation of nimodipine elimination half-life and a reduction in plasma clearance of the drug compared with healthy individuals. These findings may have been attributable in part to age related reductions in liver function in patients with renal impairment, who were substantially older (mean age 65.3 years) than healthy controls (mean age 25.2 years). An additional study in patients with different degrees of creatinine clearance suggests no systemic accumulation of the drug.

5.3 Preclinical Safety Data

Genotoxicity.

Nimodipine was not mutagenic when tested in bacteria (S. typhimurium strains TA98, TA100, TA1535 and TA1537) and yeast (Saccharomyces cerevisiae). Weak clastogenicity was observed in vitro in assays with Chinese Hamster ovary cells in the presence of metabolic activation, but chromosomal damage was not evident in vivo in either the mouse micronucleous test or the dominant lethal test.

Carcinogenicity.

Nimodipine was not tumorigenic in male and female mice treated with oral doses up to 546 and 774 mg/kg/day, respectively, for 21 months (estimated relative exposure, 7-10 based on mg/m² body surface area). No treatment-related increase in the incidence of tumours was observed in rats administered oral doses of nimodipine of up to 91 mg/kg/day (males) or 121 mg/kg/day (females) for 2 years (estimated relative exposure, 2-3 based on mg/m² body surface area).

6 Pharmaceutical Particulars

6.1 List of Excipients

Nimodipine Juno concentrated intravenous infusion solution contains ethanol (200 mg/mL), macrogol 400, sodium citrate dihydrate, citric acid and water for injections as excipients.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Nimodipine Juno concentrated intravenous infusion solution has good stability, but is somewhat sensitive to light, and therefore must not be used in direct sunlight. The product should be stored in the manufacturer's light-protective glass bottle container within the cardboard carton. 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, Nimodipine Juno concentrated intravenous infusion solution can be used for up to 10 hours without protection from light. Protect from freezing. Store below 25°C.

6.5 Nature and Contents of Container

Nimodipine Juno concentrated intravenous infusion solution.
Clear slightly yellowish solution containing 10 mg nimodipine/50 mL contained in a topaz glass vial with a grey rubber closure and sealed with a flip off top. Pack of 1 glass vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical name: Nimodipine is isopropyl (2 - methoxyethyl) 1, 4 - dihydro - 2, 6 - dimethyl - 4 - (3 - nitrophenyl) - 3, 5 - pyridine - dicarboxylate.

Chemical structure.

CAS number.

66085-59-4.
Molecular weight: 418.5.
Molecular formula: C₂₁H₂₆N₂O₇.

7 Medicine Schedule (Poisons Standard)

Schedule 4 Prescription only Medicine.

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