Consumer medicine information

Fosaprepitant Medsurge

Fosaprepitant

BRAND INFORMATION

Brand name

Fosaprepitant Medsurge

Active ingredient

Fosaprepitant

Schedule

SUMMARY CMI

Fosaprepitant Medsurge

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 being given Fosaprepitant Medsurge?

Fosaprepitant Medsurge contains the active ingredient Fosaprepitant dimeglumine. Fosaprepitant Medsurge in combination with other medicines, is used to prevent nausea (feeling sick) and vomiting associated with cancer chemotherapy.

For more information, see Section 1. Why am I being given Fosaprepitant Medsurge? in the full CMI.

2. What should I know before I am given Fosaprepitant Medsurge?

Do not use if you have ever had an allergic reaction to Fosaprepitant Medsurge, aprepitant or any of the ingredients listed at the end of this leaflet.

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

For more information, see Section 2. What should I know before I am given Fosaprepitant Medsurge? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Fosaprepitant Medsurge 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 am I given Fosaprepitant Medsurge?

Fosaprepitant Medsurge is to be given intravenously by your doctor and it contains 150 mg of fosaprepitant as the active ingredient.
Fosaprepitant Medsurge 150 mg may be given to you as an infusion over 20-30 minutes approximately 30 minutes before you start your chemotherapy treatment.

More instructions can be found in Section 4. How am I given Fosaprepitant Medsurge? in the full CMI.

5. What should I know while being given Fosaprepitant Medsurge?

Things you should do	Women taking oral contraceptive pills for birth control should also use other methods of contraception during treatment with Fosaprepitant Medsurge and for one month following the last dose of Fosaprepitant Medsurge.
Things you should not do	Do not use Fosaprepitant Medsurge if: the packaging is torn or shows signs of tampering and the expiry date on the pack has passed.
Driving or using machines	Be careful driving or operating machinery until you know how Fosaprepitant Medsurge affects you. Fosaprepitant Medsurge generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many medicines, it may cause certain side effects in some people, including tiredness and dizziness.

For more information, see Section 5. What should I know while being given Fosaprepitant Medsurge? in the full CMI.

6. Are there any side effects?

Tell your doctor if you experience any of the following - tiredness, generally feeling unwell, muscle weakness, headache, dizziness, slow, fast or irregular heartbeat, severe upper stomach pain, symptoms of severe sunburn, such as redness, itching, pain, swelling or blistering, severe skin reactions, including the inside of the nose or mouth, serious decrease of blood pressure. Other side effects not listed above may also occur in some people.

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

Fosaprepitant Medsurge

Active ingredient(s): Fosaprepitant (as dimeglumine)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Fosaprepitant Medsurge. 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 Fosaprepitant Medsurge.

Where to find information in this leaflet:

1. Why am I being given Fosaprepitant Medsurge?
2. What should I know before I am given Fosaprepitant Medsurge?
3. What if I am taking other medicines?
4. How am I given Fosaprepitant Medsurge?
5. What should I know while being given Fosaprepitant Medsurge?
6. Are there any side effects?
7. Product details

1. Why am I being given Fosaprepitant Medsurge?

Fosaprepitant Medsurge contains the active ingredient Fosaprepitant (as dimeglumine).

Fosaprepitant belongs to a group of medicines called neurokinin 1 (NK1) receptor antagonists. It works by blocking the actions of substances in your brain, called substance P neurokinins, that cause nausea and vomiting.

Fosaprepitant Medsurge in combination with other medicines, is used to prevent nausea (feeling sick) and vomiting associated with cancer chemotherapy.

Your doctor may have prescribed Fosaprepitant Medsurge for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

This medicine is not addictive.

2. What should I know before I am given Fosaprepitant Medsurge?

Warnings

Do not use Fosaprepitant Medsurge if:

you are allergic to fosaprepitant dimeglumine, aprepitant or any of the ingredients listed at the end of this leaflet leaflet. Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have or have had any other medical conditions.
have any allergies to any other medicines or any other substances such as foods, preservatives or dyes

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. Fosaprepitant Medsurge has not been studied in pregnant women. Fosaprepitant Medsurge should be used during pregnancy only if clearly needed.

Do not use Fosaprepitant Medsurge if you are breastfeeding or intend to breastfeed. It is not known if Fosaprepitant Medsurge passes into breast milk. You and your doctor should discuss whether you should stop breast-feeding or not be given Fosaprepitant Medsurge.

If you have not told your doctor about any of the above, tell them before you are given any Fosaprepitant Medsurge.

Children and Adolescents

The safety and effectiveness of Fosaprepitant Medsurge in children and teenagers under the age of 18 years have not been established.

3. What if I am taking other medicines?

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

Some medicines should not be taken with Fosaprepitant Medsurge. These include:

cisapride, used to treat stomach reflux
pimozide, used to treat psychotic conditions
terfenadine (Teldane^#) and astemizole (Hismanal^#), antihistamines used for allergic conditions, including hayfever
^# not available in Australia
St John's Wort - a herb used to treat depression

Using Fosaprepitant Medsurge with these medicines may cause serious or life-threatening reactions.

Some medicines may interfere with Fosaprepitant Medsurge and affect how it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you. These include:

warfarin, used to prevent blood clots. Your doctor may order additional blood tests to check the effect of warfarin after you have been given Fosaprepitant Medsurge.
rifampicin, an antibiotic used to treat tuberculosis and other infections
ketoconazole, used to treat fungal infections
oral contraceptive pills (also known as the pill). Alternative or "back-up" measures of contraception should be used during treatment with Fosaprepitant Medsurge and for one month following the last dose of Fosaprepitant Medsurge.
paroxetine, used to treat depression, and obsessive compulsive and panic disorders
diltiazem, used to treat angina and high blood pressure
midazolam, triazolam, or alprazolam, used as sedatives or to treat anxiety or panic disorder
dexamethasone or methylprednisolone, steroid medicines used for a variety of conditions
certain cancer chemotherapy agents, including etoposide, vinorelbine, paclitaxel
tolbutamide, used to treat diabetes
phenytoin, used to treat epilepsy

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

4. How am I given Fosaprepitant Medsurge?

When is Fosaprepitant Medsurge given

Fosaprepitant Medsurge will be administered by your doctor or nurse, on the day of chemotherapy.
Fosaprepitant Medsurge will be given as an infusion into your vein approximately 30 minutes before the start of your chemotherapy treatment.

If you use too much Fosaprepitant Medsurge

As Fosaprepitant Medsurge will most likely be given to you in hospital or clinic, it is very unlikely that you will receive an overdose. However if you experience severe side effects tell your doctor immediately.

If you think that you have been given too much Fosaprepitant Medsurge, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre (by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while being given Fosaprepitant Medsurge?

Things you should do

Call your doctor straight away if:

you become pregnant while using Fosaprepitant Medsurge.
you are about to be started on any new medicine.

Women taking oral contraceptive pills for birth control should also use other methods of contraception during treatment with Fosaprepitant Medsurge and for one month following the last dose of Fosaprepitant Medsurge.

This is because oral contraceptive pills may not work as well when using Fosaprepitant Medsurge.

Things you should not do

Managing your chemotherapy induced nausea and vomiting

Small, frequent meals or eating a snack before your chemotherapy treatment may help you to tolerate it better.

Talk to your doctor, pharmacist or nurse for more information.

Driving or using machines

Be careful driving or operating machinery until you know how Fosaprepitant Medsurge affects you.

Fosaprepitant Medsurge generally does not cause any problems with your ability to drive a car or operate machinery.

However, as with many medicines, it may cause certain side effects in some people, including tiredness and dizziness. Make sure you know how you react to Fosaprepitant Medsurge before you drive a car or operate machinery.

Looking after your medicine

Fosaprepitant Medsurge will be stored in the pharmacy or on the ward.
It is kept in a refrigerator where the temperature stays between 2-8°C.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

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.

Do not be alarmed by the following list of side effects. You may not experience any of them.

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

Less serious side effects

Less serious side effects	What to do
tiredness generally feeling unwell muscle weakness headache dizziness constipation diarrhoea indigestion heartburn loss of appetite gas from the stomach or bowel wind hiccups/hiccoughs vomiting disorientation chills hot flushes bloating pain on urination changes to your walking pattern acne injection site pain hardening at the injection site redness and/or itching at infusion site	Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

slow, fast or irregular heart beat
severe upper stomach pain
symptoms of severe sunburn, such as redness, itching, pain, swelling or blistering which may occur at or near the site of infusion.
signs of anaemia such as, being short of breath when exercising, looking pale
frequent signs of infections such as fever, severe chills, sore throat or mouth ulcers
swelling of the face, lips, mouth, throat or neck which may cause difficulty breathing or swallowing
pinkish, itchy swellings on the skin, also called hives or nettlerash
severe skin reactions, including the inside of the nose or mouth
serious decrease of blood pressure

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 affects 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 Fosaprepitant Medsurge contains

Active ingredient (main ingredient)	Fosaprepitant dimeglumine
Other ingredients (inactive ingredients)	disodium edetate lactose polysorbate 80 sodium hydroxide (for pH adjustment) hydrochloric acid (for pH adjustment)

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

What Fosaprepitant Medsurge looks like

Fosaprepitant Medsurge white to off white lyophilized cake or powder. After reconstitution with 5 mL 0.9% sodium chloride injection, it is clear, colourless to light yellow coloured solution free from visible particles.

Fosaprepitant Medsurge 150 mg powder for injection is packaged in a 10 mL Type I clear glass vial, closed with a bromobutyl rubber stopper and an aluminium seal.

Pack size: 1 vial. (AUST R 401534)

Who distributes Fosaprepitant Medsurge

Marketed and Distributed by Medsurge Healthcare.
Telephone: 1300 788 261
Website: www.medsurgehc.com

This leaflet was prepared in Dec 2023.

Published by MIMS May 2024

BRAND INFORMATION

Brand name

Fosaprepitant Medsurge

Active ingredient

Fosaprepitant

Schedule

1 Name of Medicine

Fosaprepitant (as dimeglumine).

2 Qualitative and Quantitative Composition

Each vial of Fosaprepitant Medsurge 150 mg for intravenous administration contains 245.3 mg of fosaprepitant dimeglumine equivalent to 150 mg fosaprepitant free acid.

List of excipients with known effect.

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

3 Pharmaceutical Form

Fosaprepitant Medsurge is white to off white lyophilized cake or powder. After reconstitution with 5 mL 0.9% sodium chloride injection, it is clear, colourless to light yellow coloured solution free from visible particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Fosaprepitant Medsurge, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of:
highly emetogenic cancer chemotherapy (see Section 4.2 Dose and Method of Administration);
moderately emetogenic cancer chemotherapy (see Section 4.2 Dose and Method of Administration).

4.2 Dose and Method of Administration

Dosage recommendations.

Fosaprepitant Medsurge, for administration by intravenous infusion, is a lyophilised prodrug of aprepitant containing polysorbate 80 (PS80).

Fosaprepitant Medsurge 150 mg.

Fosaprepitant Medsurge 150 mg is administered on day 1 as an infusion over 20-30 minutes initiated approximately 30 minutes prior to chemotherapy. Fosaprepitant Medsurge should be administered in conjunction with a corticosteroid and a 5-HT₃ antagonist as specified in Table 1 and Table 2. The package insert for the co-administered 5-HT₃ antagonist must be consulted prior to initiation of treatment with Fosaprepitant Medsurge 150 mg.

Preparation of Fosaprepitant Medsurge 150 mg.

1. Inject 5 mL saline into the vial. Assure that saline is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting saline into the vial.
2. Prepare an infusion bag filled with 145 mL of saline.
3. Withdraw the entire volume from the vial and transfer it into an infusion bag containing 145 mL of saline to yield a total volume of 150 mL. Gently invert the bag 2-3 times.*
4. To avoid microbiological hazard, the Fosaprepitant Medsurge solution should be used as soon as practicable after reconstitution and further dilution. If storage is unavoidable, the solution should be held at 2-8°C for not more than 24 hours.
5. Parenteral drug products should be inspected visually for particulate matter and discolouration before administration whenever solution and container permit.
6. Fosaprepitant Medsurge 150 mg should only be administered as an infusion over 20-30 minutes.
Product is for single use in one patient only. Discard any residue.
* Please Note: there is a 5% overage in each vial to account for non-withdrawable losses and to ensure that the labelled dose of 150 mg is deliverable after reconstitution.

General information.

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for additional information on the administration of Fosaprepitant Medsurge with corticosteroids.
Refer to the full prescribing information for coadministered antiemetic agents.
No dosage adjustment is necessary based on age, gender, race, or Body Mass Index.
No dosage adjustment is necessary for patients with severe renal insufficiency (creatinine clearance < 30 mL/min) or for patients with end stage renal disease undergoing haemodialysis.
No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score > 9).

4.3 Contraindications

Fosaprepitant Medsurge is contraindicated in patients who are hypersensitive to fosaprepitant, aprepitant, polysorbate 80 or any other components of the product.
Fosaprepitant Medsurge should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Since fosaprepitant is rapidly converted to aprepitant, which is a dose dependent inhibitor of CYP3A4, fosaprepitant should be used with caution in patients receiving concomitant orally administered medicinal products that are primarily metabolized through CYP3A4; some chemotherapy agents are metabolized by CYP3A4 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Weak inhibition of CYP3A4 by fosaprepitant 150 mg could result in elevated plasma concentrations of these concomitant medicinal products (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Immediate hypersensitivity reactions including flushing, erythema, rash, chest tightness, wheezing, dyspnea and anaphylaxis/anaphylactic shock have occurred during or soon after infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who experience hypersensitivity reactions.
Infusion site reactions (ISRs) have been reported with the use of fosaprepitant (see Section 4.8 Adverse Effects (Undesirable Effects)). The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (e.g. anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy.
Coadministration of fosaprepitant with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The efficacy of hormonal contraceptives during and for 28 days after administration of fosaprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant and for 1 month following administration of fosaprepitant (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Fosaprepitant should not be given as a bolus injection but should always be diluted and given as a slow intravenous infusion (see Section 4.2 Dose and Method of Administration). Fosaprepitant should not be administered intramuscularly or subcutaneously. Mild injection site thrombosis has been observed at higher doses (see Section 4.9 Overdose). If signs or symptoms of local irritation occur, the injection or infusion should be terminated and restarted in another vein.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties, Elderly.

Paediatric use.

See Section 5.2 Pharmacokinetic Properties, Paediatric patients.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, INR monitoring as mentioned above; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Warfarin.

4.5 Interactions with Other Medicines and Other Forms of Interactions

When administered intravenously, fosaprepitant is rapidly converted to aprepitant. Therefore, drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. The following information was derived from studies conducted with oral aprepitant and studies conducted with fosaprepitant coadministered with dexamethasone, midazolam or diltiazem.
Aprepitant is a substrate, a weak to moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also a moderate inducer of CYP2C9.
Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4, and does not induce CYP3A4. It is anticipated that fosaprepitant 150 mg would cause less or no greater induction of CYP2C9 than that caused by the administration of oral aprepitant.

Effect of fosaprepitant/aprepitant on the pharmacokinetics of other agents.

Aprepitant, as a weak to moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of orally coadministered medicinal products that are metabolised through CYP3A4.
Fosaprepitant should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions (see Section 4.3 Contraindications). Caution should be exercised in using aprepitant concurrently with drugs which have a narrow therapeutic index and are known to be metabolised primarily by CYP3A4, such as ciclosporin, sirolimus and tacrolimus.
Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of fosaprepitant with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.
Fosaprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin in a clinical drug interaction study.
5-HT₃ antagonists. In clinical drug interaction studies, aprepitant when given as a regimen of 125 mg on day 1 and 80 mg on days 2 and 3, did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).
Corticosteroids.

Dexamethasone.

Fosaprepitant 150 mg administered as a single intravenous dose on day 1 increased the AUC_0-24hr of dexamethasone, a CYP3A4 substrate, by approximately 2.0-fold on days 1 and 2 when dexamethasone was coadministered as a single 8 mg oral dose on days 1, 2, and 3. The oral dexamethasone dose on days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg IV on day 1 to achieve exposures of dexamethasone similar to those obtained when given without fosaprepitant 150 mg (see Section 4.2 Dose and Method of Administration).

Methylprednisolone.

Oral aprepitant, when given as a regimen of 125 mg on day 1 and 80 mg/day on days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-fold on day 1 and by 2.5-fold on day 3, when methylprednisolone was coadministered intravenously as 125 mg on day 1 and orally as 40 mg on days 2 and 3.
Chemotherapeutic agents. Chemotherapy agents that are known to be metabolised by the CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, oral aprepitant (125 mg/80 mg regimen) was administered commonly with etoposide, vinorelbine, and paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. Adequate data are not available on interactions between aprepitant and other chemotherapy agents primarily metabolised by CYP3A4. Particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolised primarily by CYP3A4. Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide coadministration (see Section 4.4 Special Warnings and Precautions for Use).

Docetaxel.

In an interaction study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel.

Vinorelbine.

In a separate pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine.
Formal interaction studies have not been conducted with other chemotherapy agents.
Warfarin. A single 125 mg dose of oral aprepitant was administered on day 1 and 80 mg/day on days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on day 3, there was a 34% decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant.
In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle.
Tolbutamide. Oral aprepitant, when given as 125 mg on day 1 and 80 mg/day on days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on day 4, 28% on day 8, and 15% on day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on days 4, 8, and 15.
Oral contraceptives. Aprepitant, when given once daily for 14 days as a 100 mg capsule with an oral contraceptive containing 35 microgram of ethinylestradiol and 1 mg of norethindrone, decreased the AUC of ethinylestradiol by 43%, and decreased the AUC of norethindrone by 8%.
In another study, a single dose of an oral contraceptive containing ethinylestradiol and norethindrone was administered on days 1 through 21 with oral aprepitant, given as a regimen of 125 mg on day 8 and 80 mg/day on days 9 and 10 with ondansetron 32 mg IV on day 8 and oral dexamethasone given as 12 mg on day 8 and 8 mg/day on days 9, 10, and 11. In the study, the AUC of ethinylestradiol decreased by 19% on day 10 and there was as much as a 64% decrease in ethinylestradiol trough concentrations during days 9 through 21. While there was no effect of oral aprepitant on the AUC of norethindrone on day 10, there was as much as a 60% decrease in norethindrone trough concentrations during days 9 through 21.
The efficacy of hormonal contraceptives during and for 28 days after administration of fosaprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant and for 1 month following administration of fosaprepitant.
Midazolam. Fosaprepitant 150 mg administered as a single intravenous dose on day 1 increased the AUC_0-∞ of midazolam by approximately 1.8-fold on day 1 and had no effect (1.0-fold) on day 4 when midazolam was coadministered as a single oral dose of 2 mg on days 1 and 4. Fosaprepitant 150 mg IV is a weak CYP3A4 inhibitor as a single dose on day 1 with no evidence of inhibition or induction of CYP3A4 observed on day 4.

Effect of other agents on the pharmacokinetics of aprepitant.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant with strong CYP3A4 inhibitors (e.g. ketoconazole) should be approached cautiously; but concomitant administration of aprepitant with moderate CYP3A4 inhibitors (e.g. diltiazem) does not result in clinically meaningful changes in plasma concentrations of aprepitant.
Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant with drugs that strongly induce CYP3A4 activity (e.g. rifampin) may result in reduced plasma concentrations and decreased efficacy. Concomitant administration of fosaprepitant with St. John's Wort is not recommended.

Ketoconazole.

When a single 125 mg dose of oral aprepitant was administered on day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant with strong CYP3A4 inhibitors should be approached cautiously.

Rifampicin.

When a single 375 mg dose of oral aprepitant was administered on day 9 of a 14-day regimen of 600 mg/day of rifampicin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of fosaprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy.

Additional interactions.

Diltiazem.

In patients with mild to moderate hypertension, infusion of 100 mg fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. The pharmacokinetic effects resulted in a small but clinically meaningful decrease in diastolic blood pressure (decrease of 16.8 mmHg with fosaprepitant versus 10.5 mmHg without fosaprepitant) and may result in a small but clinically meaningful decrease in systolic blood pressure (decrease of 24.4 mmHg with fosaprepitant versus 18.8 mmHg without fosaprepitant) but did not result in a clinically meaningful change in heart rate, or PR interval, beyond those changes induced by diltiazem alone.

Paroxetine.

Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and C_max by approximately 20% of both aprepitant and paroxetine.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant, particularly in rats. The effect of fosaprepitant on fertility has not been established at exposures expected with clinical use of the drug. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant.
Aprepitant administered to male or female rats at oral doses up to 1,000 mg/kg twice daily (approximately 1.5 times the adult human dose based on systemic exposure following oral aprepitant 125 mg in females, or lower than the adult human dose in males) had no effects on mating performance, fertility, or embryonic/foetal survival. Sperm count and motility were unaffected in males.
(Category B2)
Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant, particularly in the species used in the reproductive toxicity studies and the potential teratogenicity of fosaprepitant at exposures equivalent to those expected with clinical use has not been established. In the teratology studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant.
Reproductive studies with oral aprepitant have been performed in rats and rabbits at doses up to 1.5 times the systemic exposure at the adult human dose following oral aprepitant 125 mg and have revealed no evidence of harm to the foetus. Given that there are no adequate and well-controlled studies in pregnant women and that the potential teratogenicity of fosaprepitant at exposures equivalent to those expected with clinical use has not been established, this drug should not be used during pregnancy unless the clinical benefit to the mother outweighs any potential harm to the foetus.
Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant.
Significant concentrations of aprepitant were observed in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the possible adverse effects of aprepitant on nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. However, certain side effects that have been reported with fosaprepitant may affect some patients' ability to drive or operate machinery. Individual responses to Fosaprepitant Medsurge may vary.

4.8 Adverse Effects (Undesirable Effects)

The overall safety of fosaprepitant was evaluated in approximately 1600 individuals.

Moderately emetogenic chemotherapy (MEC).

In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients receiving a single dose of fosaprepitant in combination with ondansetron and dexamethasone (fosaprepitant regimen) compared to 497 patients receiving ondansetron and dexamethasone alone (control regimen). The following clinically important drug-related adverse experiences were reported in patients treated with the fosaprepitant regimen and at a greater incidence than in the control group.
[Common (≥ 1/100, < 1/10), Uncommon (≥ 1/1000, < 1/100)].

Cardiac disorders.

Uncommon: palpitations.

Gastrointestinal disorders.

Common: constipation.
Uncommon: abdominal distension, abdominal pain, abdominal pain upper, dyspepsia.

General disorders and administration site conditions.

Common: infusion site pain.
Uncommon: asthenia.

Infections and infestations.

Uncommon: oral candidiasis.

Metabolism and nutrition disorders.

Uncommon: decreased appetite.

Respiratory, thoracic and mediastinal disorders.

Uncommon: cough, oropharyngeal pain, throat irritation.

Vascular disorders.

Uncommon: hot flush.

Highly emetogenic chemotherapy (HEC).

In an active-controlled clinical study in patients receiving highly emetogenic chemotherapy, safety was evaluated for 1143 patients receiving a single dose of fosaprepitant 150 mg compared to 1169 patients receiving the 3-day regimen of aprepitant. The safety profile was generally similar to that seen in the MEC study with fosaprepitant.
The following additional clinically important drug-related adverse experiences occurred with fosaprepitant 150 mg and have not been reported in earlier clinical studies with oral aprepitant, or in the MEC study with fosaprepitant.
[Uncommon (≥ 1/1000, < 1/100), Rare (≥ 1/10,000, < 1/1,000)].

General disorders and administration site conditions.

Uncommon: infusion site erythema, infusion site pruritus.
Rare: infusion site induration.

Investigations.

Uncommon: blood pressure increased.

Skin and subcutaneous tissue disorders.

Uncommon: erythema.

Vascular disorders.

Uncommon: flushing, thrombophlebitis (predominantly, infusion-site thrombophlebitis).

Aprepitant adverse effects.

Since fosaprepitant is converted to aprepitant, those adverse experiences associated with aprepitant might also be expected to occur with fosaprepitant.
The overall safety of aprepitant was evaluated in approximately 6500 individuals.
Prevention of chemotherapy induced nausea and vomiting (CINV). In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy (HEC), 544 patients were treated with the 3-day oral aprepitant regimen during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. In 2 well-controlled clinical trials in patients receiving moderately emetogenic cancer chemotherapy, 868 patients were treated with the 3-day oral aprepitant regimen during Cycle 1 of chemotherapy and 686 of these patients continued into the Multiple-Cycle extensions for up to 4 cycles of chemotherapy. The 3-day oral aprepitant regimen was given in combination with ondansetron and dexamethasone and was generally well tolerated. Most adverse experiences reported in these clinical studies were described as mild to moderate in intensity.
Highly emetogenic chemotherapy (HEC). In Cycle 1, in patients receiving HEC, drug-related clinical adverse experiences were reported in approximately 19% of patients treated with the 3-day oral aprepitant regimen, compared with approximately 14% of patients treated with standard therapy. Treatment was discontinued due to drug-related clinical adverse experiences in 0.6% of patients treated with the 3-day oral aprepitant regimen, compared with 0.4% of patients treated with standard therapy. Table 3 shows the drug-related adverse experiences reported at an incidence ≥ 0.5% (and at a greater incidence than standard therapy) in patients treated with the 3-day oral aprepitant regimen.

In an additional active-controlled clinical study in 1169 patients receiving the 3-day oral aprepitant regimen and HEC, the adverse experience profile was generally similar to that seen in the other HEC studies with the 3-day oral aprepitant regimen.
Moderately emetogenic chemotherapy (MEC). In the combined analysis of Cycle 1 data in patients receiving MEC, drug-related adverse experiences were reported in approximately 14% of patients treated with the 3-day oral aprepitant regimen compared with approximately 15% of patients treated with standard therapy. Treatment was discontinued due to drug-related adverse experiences in 0.7% of patients treated with the 3-day oral aprepitant regimen compared with 0.2% of patients treated with standard therapy. Table 4 shows the drug-related adverse experiences reported at an incidence ≥ 0.5% and at a greater incidence than standard therapy in patients treated with the 3-day oral aprepitant regimen.

Highly and moderately emetogenic chemotherapy. In a pooled analysis of the HEC and MEC studies, the following drug-related adverse experiences were reported in patients treated with the 3-day oral aprepitant regimen at a greater incidence than standard therapy and not described above:

Blood and lymphatic system disorders.

Febrile neutropenia.

Infection and infestations.

Candidiasis, staphylococcal infection.

Metabolism and nutrition disorders.

Polydipsia.

Psychiatric disorders.

Disorientation, euphoric mood.

Nervous system disorders.

Cognitive disorder, lethargy, dysgeusia.

Eye disorders.

Conjunctivitis.

Ear and labyrinth disorders.

Tinnitus.

Cardiac disorders.

Cardiovascular disorder, bradycardia, palpitations.

Vascular disorders.

Hot flush.

Respiratory, thoracic and mediastinal disorders.

Cough, oropharyngeal pain, postnasal drip, sneezing, throat irritation.

Gastrointestinal disorders.

Abdominal distension, dry mouth, faeces hard, flatulence, neutropenic colitis, duodenal ulcer perforation, stomatitis, vomiting.

Skin and subcutaneous tissue disorders.

Acne, hyperhidrosis, seborrhoea, photosensitivity reaction, rash pruritic, rash, skin lesion.

Musculoskeletal and connective tissue disorders.

Muscular weakness, muscle spasms.

Renal and urinary disorders.

Dysuria, pollakiuria.

General disorders and administration site conditions.

Chest discomfort, oedema, gait disturbance, malaise.

Investigations.

Blood sodium decreased, red blood cells urine positive, neutrophil count decreased, weight decreased, glucose urine present, urine output increased.
The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to those observed in Cycle 1.
In other clinical studies, isolated cases of serious adverse experiences were reported. In another chemotherapy induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy. Angioedema and urticaria were reported in a patient receiving aprepitant in a non-CINV study.
Oral administration of a single 165 mg dose of aprepitant was generally well tolerated in healthy adults.
Based on a comparable pharmacokinetic/pharmacodynamic profile, the 1-day oral regimen of aprepitant 165 mg administered in the fasted state or with a light (low fat) meal is anticipated to have a similar safety and tolerability profile to that of the 1-day regimen of fosaprepitant 150 mg and the 3-day oral aprepitant regimen in chemotherapy patients (see Section 5 Pharmacological Properties).
Laboratory adverse experiences. One laboratory adverse experience, haemoglobin decreased (40 mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥ 3% in a patient receiving general anaesthesia.
The following additional laboratory adverse experiences (incidence > 0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present.
The adverse experience of ALT increased occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%).
Other studies. Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study.

Post-marketing experience.

The following adverse reactions have been identified during post-marketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug.

Skin and subcutaneous tissue disorders.

Pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders.

Hypersensitivity reactions including anaphylactic reactions/anaphylactic shock.
Immediate hypersensitivity or anaphylactic reactions have been observed during the infusion of fosaprepitant which may include the following: flushing, erythema, rash, chest tightness, wheezing, dyspnoea (see Section 4.4 Special Warnings and Precaution for Use).

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

No specific information is available on the treatment of overdosage. Single doses up to 200 mg of fosaprepitant IV and 600 mg of aprepitant were generally well tolerated in healthy subjects. Three out of 33 subjects receiving 200 mg of fosaprepitant experienced mild injection site thrombosis. Aprepitant was generally well tolerated when administered as 375 mg once daily for up to 42 days to patients in non-CINV studies. In 33 cancer patients, administration of a single 375 mg dose of aprepitant on day 1 and 250 mg once daily on days 2 to 5 was generally well tolerated.
Drowsiness and headache were reported in one patient who ingested 1440 mg of aprepitant.
In the event of overdose, Fosaprepitant Medsurge should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective.
Aprepitant cannot be removed by haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.
Aprepitant has a unique mode of action; it is a selective high affinity antagonist at human substance P neurokinin 1 (NK₁) receptors. Counter-screening assays showed that aprepitant was at least 3,000-fold selective for the NK₁ receptor over other enzyme, transporter, ion channel and receptor sites including the dopamine and serotonin receptors that are the targets of existing therapy for chemotherapy-induced nausea and vomiting (CINV).
NK₁-receptor antagonists have been shown pre-clinically to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Preclinical and human positron emission tomography (PET) studies with aprepitant have shown that it is brain penetrant and occupies brain NK₁ receptors. Preclinical studies show that aprepitant has a long duration of central activity, inhibits both the acute and delayed phases of cisplatin-induced emesis, and augments the antiemetic activity of the 5-HT₃-receptor antagonist ondansetron and the corticosteroid dexamethasone against cisplatin-induced emesis.

Cardiac electrophysiology.

In a randomised, double-blind, positive controlled, thorough QTc study, a single 200 mg dose of fosaprepitant had no effect on the QTc interval.

Brain NK₁ receptor occupancy assessed by positron emission tomography.

A positron emission tomography study in healthy young men administered a single intravenous dose of 150 mg fosaprepitant (N=8) demonstrated brain NK₁ receptor occupancy of ≥ 100% at T_max, and 24 hours, ≥ 97% at 48 hours, and between 41% and 75% at 120 hours, following dosing. Occupancy of brain NK₁ receptors, in this study, correlate well with aprepitant plasma concentrations.

Clinical trials.

Prevention of chemotherapy induced nausea and vomiting (CINV).

Highly emetogenic chemotherapy (HEC).

In a randomised, parallel, double-blind, active-controlled study, fosaprepitant 150 mg (N=1147) as a single intravenous infusion was compared with a 3-day aprepitant regimen (N=1175) in patients receiving a highly emetogenic chemotherapy regimen that included cisplatin (≥ 70 mg/m²). Other concomitant chemotherapy agents commonly administered were fluorouracil, gemcitabine, paclitaxel, and etoposide. All patients in both groups received dexamethasone and ondansetron (see Table 5).

Efficacy was based on the evaluation of the following composite measures: complete response in both the overall and delayed phases and no vomiting in the overall phase. fosaprepitant 150 mg was shown to be non-inferior to that of the 3-day regimen of aprepitant. A summary of the primary and secondary endpoints is shown in Table 6.

Moderately emetogenic chemotherapy (MEC).

In a randomized, parallel, double-blind, active comparator-controlled study, fosaprepitant 150 mg as a single intravenous infusion (N=502) in combination with ondansetron and dexamethasone (fosaprepitant regimen) was compared with ondansetron and dexamethasone alone (control regimen) (N=498) (see Table 7) in patients receiving a moderately emetogenic chemotherapy regimen. The most commonly administered MEC chemotherapeutic agents were carboplatin, oxaliplatin, and cyclophosphamide.

The efficacy of fosaprepitant was evaluated based on the primary and secondary endpoints listed in Table 8 and was shown to be superior to the control regimen with regard to complete response in the delayed and overall phases.

The Kaplan-Meier curves in Figure 1 show that the time to first vomiting was longer in subjects in the fosaprepitant regimen compared with the control regimen (nominal p-value < 0.001 by log-rank test).

5.2 Pharmacokinetic Properties

Absorption.

Fosaprepitant is dosed intravenously and therefore is immediately and completely bioavailable.

Aprepitant after fosaprepitant administration.

Following a single intravenous 150 mg dose of fosaprepitant administered as a 20-minute infusion to healthy volunteers the mean AUC_0-∞ of aprepitant was 35.0 microgram.hr/mL and the mean maximal aprepitant concentration was 4.01 microgram/mL.

Distribution.

Fosaprepitant is rapidly converted to aprepitant. Aprepitant is greater than 95% bound to plasma proteins. The geometric mean apparent volume of distribution at steady state (Vd_ss) is approximately 66 L in humans.
Aprepitant crosses the placenta in rats and crosses the blood brain barrier in rats and ferrets. PET studies in humans indicate that aprepitant crosses the blood brain barrier (see Section 5.1 Pharmacodynamic Properties, Mechanism of action).

Metabolism.

Fosaprepitant was rapidly converted to aprepitant in in vitro incubations with liver preparations from nonclinical species (rat and dog) and humans. Furthermore, fosaprepitant underwent rapid and nearly complete conversion to aprepitant in S9 preparations from multiple other human tissues including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple extrahepatic tissues in addition to the liver. In humans, fosaprepitant administered intravenously was rapidly converted to aprepitant within 30 minutes following the end of infusion.
Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300 mg dose of [¹⁴C]-aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains. In vitro studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19, and no metabolism by CYP2D6, CYP2C9, or CYP2E1.
All metabolites observed in urine, faeces and plasma following an intravenous 100 mg [¹⁴C]-fosaprepitant dose were also observed following an oral dose of [¹⁴C]-aprepitant. Upon conversion of 245.3 mg of fosaprepitant dimeglumine (equivalent to 150 mg fosaprepitant free acid) to aprepitant, 23.9 mg of phosphoric acid and 95.3 mg of meglumine are liberated.

Excretion.

Following administration of a single IV 100 mg dose of [¹⁴C]-fosaprepitant to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in faeces.
Aprepitant is eliminated primarily by metabolism. No aprepitant is excreted unchanged in the urine. Following administration of a single oral 300 mg dose of [¹⁴C]-aprepitant to healthy subjects, 5% of the radioactivity was recovered in urine and 86% in faeces.
The mean apparent terminal half-life of aprepitant following fosaprepitant administration was approximately 14 hours.

Special populations.

Gender.

Following oral administration of a single dose of aprepitant, the AUC_0-24hr and C_max for aprepitant are 9% and 17% higher, respectively in females as compared with males. The half-life of aprepitant is approximately 25% lower in females as compared with males and its T_max occurs at approximately the same time. These differences are not considered clinically meaningful. No dosage adjustment is necessary based on gender.

Elderly.

Following oral administration of a single 125 mg dose of aprepitant on day 1 and 80 mg once daily on days 2 through 5, the AUC_0-24hr of aprepitant was 21% higher on day 1 and 36% higher on day 5 in elderly (≥ 65 years) relative to younger adults. The C_max was 10% higher on day 1 and 24% higher on day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful. No dosage adjustment is necessary in elderly patients.

Race.

Following oral administration of a single dose of aprepitant, the AUC_0-24hr is approximately 27% and 31% higher in Hispanics as compared with Caucasians and Blacks, respectively. The C_max is 19% and 29% higher in Hispanics as compared with Caucasians and Blacks, respectively. Single dose administration of oral aprepitant in Asians resulted in a 74% and 47% increase in AUC_0-24hr and C_max, respectively, as compared to Caucasians. These differences are not considered clinically meaningful. No dosage adjustment is necessary based on race.

Body mass index (BMI).

Body Mass Index (BMI) had no clinically meaningful effect on the pharmacokinetics of aprepitant.

Renal insufficiency.

A single 240 mg dose of oral aprepitant was administered to patients with severe renal insufficiency (CrCl < 30 mL/min) and to patients with end stage renal disease (ESRD) requiring haemodialysis.
In patients with severe renal insufficiency, the AUC_0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and C_max decreased by 32%, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC_0-∞ of total aprepitant decreased by 42% and C_max decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal insufficiency compared with healthy subjects. Haemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.
No dosage adjustment for Fosaprepitant Medsurge is necessary for patients with severe renal insufficiency or for patients with ESRD undergoing haemodialysis, based on the pharmacokinetics of aprepitant in these patients, although no clinical studies have been conducted to determine whether efficacy is affected.

Hepatic insufficiency.

Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic insufficiency is not expected to alter the conversion of fosaprepitant to aprepitant.
Oral aprepitant was well tolerated in patients with mild to moderate hepatic insufficiency. Following administration of a single 125 mg dose of oral aprepitant on day 1 and 80 mg once daily on days 2 and 3 to patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), the AUC_0-24hr of aprepitant was 11% lower on day 1 and 36% lower on day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the AUC_0-24hr of aprepitant was 10% higher on day 1 and 18% higher on day 3, as compared with healthy subjects given the same regimen. These differences in AUC_0-24hr are not considered clinically meaningful; therefore, no dosage adjustment is necessary in patients with mild to moderate hepatic insufficiency.
There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score > 9).

Paediatric patients.

Fosaprepitant has not been evaluated in patients below 18 years of age.

5.3 Preclinical Safety Data

Genotoxicity.

Fosaprepitant and aprepitant were both negative in the following genotoxicity assays: in vitro microbial and TK6 human lymphoblastoid cell mutagenesis assays, the in vitro alkaline elution/rat hepatocyte DNA strand break test, the in vitro chromosomal aberration assay in Chinese hamster ovary cells, and the in vivo mouse micronucleus assay in bone marrow.

Carcinogenicity.

Carcinogenicity studies were not conducted with fosaprepitant but studies were conducted with aprepitant in mice and rats for approximately 2 years. In mice, aprepitant was not carcinogenic at doses up to 500 mg/kg/day (approximately 2 times the adult human dose based on systemic exposure). Rats developed hepatocellular adenomas at a dose of 25 mg/kg twice daily (females) and 125 mg/kg twice daily (males), thyroid follicular cell adenomas at a dose of 125 mg/kg twice daily (females and males), and thyroid follicular cell carcinomas at a dose of 125 mg/kg twice daily (males). Systemic exposures at these doses in rats were approximately equivalent to or lower than exposures in humans at the recommended dose. Tumours of these types are considered to be a consequence of hepatic CYP enzyme induction in the rat and are consistent with changes observed in rats with other structurally and pharmacologically dissimilar compounds that have been shown to induce hepatic CYP enzymes. Consideration of the mechanisms involved in the development of these tumour types suggest that it is unlikely that there is any carcinogenic risk in humans at therapeutic dose levels of fosaprepitant or aprepitant.

6 Pharmaceutical Particulars

6.1 List of Excipients

Disodium edetate; lactose; polysorbate 80; sodium hydroxide (for pH adjustment); hydrochloric acid (for pH adjustment).

6.2 Incompatibilities

Fosaprepitant Medsurge is incompatible with any solutions containing divalent cations (e.g. Ca²⁺, Mg²⁺), including Hartman's and Lactated Ringer's Solution. Fosaprepitant Medsurge must not be reconstituted or mixed with solutions for which physical and chemical compatibility have not been established.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store at 2 to 8°C (Refrigerate. Do not freeze). Reconstituted solution is stable for 24 hours when stored at 20°C - 25°C.

6.5 Nature and Contents of Container

Fosaprepitant Medsurge 150 mg powder for injection is packaged in a 10 mL Type I clear glass vial, closed with a bromobutyl rubber stopper and an aluminium seal.

Pack size.

1 vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Fosaprepitant dimeglumine is a white to off-white amorphous powder. It is freely soluble in water.
Fosaprepitant dimeglumine is a prodrug of aprepitant and is chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate (2:1) (salt).
Its empirical formula is C₂₃H₂₂F₇N₄O₆P, 2(C₇H₁₇NO₅) with a molecular weight of 1004.83.

Chemical structure.

CAS number.

The CAS No. is 265121-04-8.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

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