Consumer medicine information

Cyramza

Ramucirumab

BRAND INFORMATION

Brand name

Cyramza

Active ingredient

Ramucirumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cyramza.

SUMMARY CMI

CYRAMZA®

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 CYRAMZA?

CYRAMZA contains the active ingredient ramucirumab (rmc) and is used to treat advanced stomach cancer (including cancer of the junction between the oesophagus and the stomach).

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

2. What should I know before I use CYRAMZA?

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

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 CYRAMZA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CYRAMZA and affect how it works.

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 and check with your doctor or pharmacist if you are not sure if these will affect CYRAMZA.

4. How will CYRAMZA be given?

  • CYRAMZA is given as an infusion (drip) into your veins over approximately 60 minutes.
  • CYRAMZA is given once every two weeks as part of the treatment cycle. Your doctor will advise how many treatment cycles you need.

More instructions can be found in Section 4. How will CYRAMZA be given? in the full CMI.

5. What should I know while using CYRAMZA?

Things you should do
  • Tell your doctor immediately if you become pregnant while being treated with CYRAMZA.
  • Tell your doctor immediately if you notice any changes in your movement or behaviour.
  • Remind any doctor, dentist or pharmacist you visit that you are being treated with CYRAMZA, especially if you are about to start a new medicine.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are being treated with CYRAMZA.
  • Tell your doctor if you develop a poorly healing wound.
  • Monitor your blood pressure regularly.
Driving or using machines
  • Be careful driving or operating machinery until you know how CYRAMZA affects you.

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

6. Are there any side effects?

Like all medicines, this medicine can cause side effects, although not everybody gets them. Becoming more prone to getting infections, diarrhoea, soreness inside your mouth, feeling tired or weak, swelling in your hands and lower legs, nose bleed, stomach pain and high blood pressure were very commonly reported in patients using CYRAMZA. Serious side effects may include clotting in your arteries which may lead to heart attack or stroke, tear or rupture in your arteries, bleeding or a tear in your gut, severe allergic reaction, or vision loss associated with headaches, confusion and seizures.

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

CYRAMZA®

Active ingredient: Ramucirumab (rmc)


Consumer Medicine Information (CMI)

This leaflet provides important information about using CYRAMZA. 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 CYRAMZA.

Where to find information in this leaflet:

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

1. Why am I using CYRAMZA?

CYRAMZA contains the active ramucirumab.

CYRAMZA belongs to a group of medicines known as antineoplastic (anti-cancer) agents. They may also be called chemotherapy medicines. It works by cutting off the blood supply that allows cancer cells to grow.

CYRAMZA may be used in combination with other chemotherapy drugs.

CYRAMZA is used to treat advanced stomach cancer (including cancer of the junction between the oesophagus and the stomach).

2. What should I know before I use CYRAMZA?

Warnings

Do not use CYRAMZA if:

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

Check with your doctor if you:

  • have any other conditions or are taking any other medicines that may increase your risk of bleeding or impact on your body's blood clotting ability. CYRAMZA may further increase your risk of bleeding.
  • have high blood pressure. Your doctor will make sure that your blood pressure is brought under control before starting CYRAMZA as it may worsen once you start treatment.
  • have severe liver disease ('cirrhosis') and associated conditions, such as excessive water retention in your stomach ('ascites'). This will help your doctor determine if CYRAMZA is right for you.
  • are going to have surgery, if you have had recent surgery, or if you have a poorly healing wound as CYRAMZA may impair your body's ability to heal itself. This will help you doctor determine when to start your treatment with CYRAMZA.
  • have or have had an enlargement and weakening of a blood vessel wall (aneurysm) or a tear in a blood vessel wall (artery dissection). This will help your doctor determine if CYRAMZA is right for you.

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?

Taking Pre-medication

Your doctor may give you another medicine in your infusion (drip) before they give you CYRAMZA. This is known as ‘pre-medication’.

Pre-medication may reduce your risk of developing an infusion-related reaction. See additional information on infusion-related reactions under Section 6. Are there any side effects

If you experience a infusion-related reaction with CYRAMZA, you will be given pre-medication for all future infusions.

Pregnancy and breastfeeding

Pregnancy and breastfeeding should be avoided during CYRAMZA treatment and for at least 3 months after the last dose of CYRAMZA. Your doctor can discuss with you the risks and benefits involved.

Use in children

This medicine is not recommended for use in children under the age of 18 years. Safety and effectiveness in children younger than 18 years have not been established.

3. What if I am taking other medicines?

Some medicines may interfere with CYRAMZA and affect how it works.

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 and check with your doctor or pharmacist if you are not sure if these will affect CYRAMZA.

4. How will CYRAMZA be given?

How much is given

Your doctor will decide the dosage of CYRAMZA you are given. This will depend on your weight.

How it is given

CYRAMZA is given as an infusion (drip) into your veins over approximately 60 minutes. You may also be given other chemotherapy medicines at the same time.

If you experience an infusion-related reaction during treatment, your doctor or nurse will increase your infusion time.

Your doctor or nurse will always prepare and administer the CYRAMZA infusion for you. You should never do this yourself.

How often is it given

CYRAMZA is given once every two weeks as part of the treatment cycle.

Your doctor will advise how many treatment cycles you will need.

If you have been given too much CYRAMZA

As CYRAMZA is given to you under the supervision of your doctor or nurse, it is unlikely that you will receive too much.

However, if you experience any unexpected or worrying side effects after being given CYRAMZA, immediately tell your doctor or nurse or go to the Emergency Department at your nearest hospital.

You may need urgent medical attention.

5. What should I know while using CYRAMZA?

Things you should do

  • Tell your doctor immediately if you become pregnant while being treated with CYRAMZA. Pregnancy and breastfeeding should be avoided during CYRAMZA treatment and for at least 3 months after the last dose of CYRAMZA.
  • Tell your doctor immediately if you notice any changes in your movement or behaviour. This may be due to a blood clot that may lead to a stroke.
  • Remind any doctor, dentist, or pharmacist that you visit that you are being treated with CYRAMZA, especially if you are about to start on any new medicine.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are being treated with CYRAMZA. CYRAMZA may impair your body's ability to heal itself. Your doctor will stop your treatment with CYRAMZA for at least 4 weeks before you have surgery and will decide when it should re-start.
  • Tell your doctor if you have any wounds that are not healing as quickly as they normally would. CYRAMZA may impair your body's ability to heal itself and your doctor may decide to temporarily stop your treatment with CYRAMZA until they have healed.
  • Monitor your blood pressure regularly while you are being treated with CYRAMZA as your blood pressure may increase during treatement. If you develop severe high blood pressure, your doctor may choose to prescribe blood pressure lowering medication or to temporarily stop your treatment with CYRAMZA until your blood pressure is under control. If your high blood pressure cannot be controlled, your doctor may choose to permanently stop your treatment with CYRAMZA.
  • Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.
  • The amount of protein in your urine will be checked regularly during your treatment with CYRAMZA. Your doctor may decide to change your dose or delay your treatement depending on your general condition and if your urine protein levels are too high. If you are passing more than a certain amount of protein with your urine or if you develop severe kidney disease, your doctor may choose to permanantley stop your treatment with CYRAMZA.
  • If you are about to have any blood tests, tell your doctor that you are receiving this medicine.

Driving or using machines

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

It is not known whether CYRAMZA will affect your ability to drive or to use machines. If you experience any symptoms that affect your ability to concentrate and react: do not drive, operate machinery, or do anything else that could be dangerous until the effect goes away.

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.

When used in combination with other chemotherapy medicine, also refer to their consumer medicine information leaflet for a list of other possible side effects.

Less serious side effects

Less serious side effectsWhat to do
General disorders:
  • swelling of the hands, feet and legs due the body retaining water
  • inflammation or soreness of the mouth
  • hoarse, rough, or raspy voice
  • Low white blood cell levels: symptoms may include fever, chills, sweating, sore throat or other signs of infection
  • feeling tired or weak, or lacking in energy
  • high blood pressure
Stomach related:
  • diarrhoea
  • stomach pain
  • blockage of the gut: symptoms may include constipation and stomach pain
Bleeding related:
  • nose bleed
  • bleeding or bruising more easily than normal
Blood-test related:
  • low blood levels of potassium which can cause muscle weakness, twitching, or abnormal heart rhythm
  • low blood levels of sodium which can cause tiredness and confusion or muscle twitching
  • low blood levels of thyroid hormone which can cause tiredness, weight gain, and feeling cold
Brain related:
  • headache
Kidney related:
  • high levels of protein in the urine: symptoms may include more frequent urination, shortness of breath, tiredness, swelling of your hands, feet, stomach or face.
Blood vessel related:
  • a collection of small blood vessels that form a lump under the skin, sometimes known as a 'strawberry mark'.
  • clotting in small blood vessels, most commonly in the kidneys or the brain. Symptoms may include confusion, sleepliness, seizures (brain), less frequent urination, swollen legs, high blood pressure (kidneys), shortness of breath, bleeding or bruising more easily, fever (both brain and kidneys).
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Stomach related:
  • hole in the wall of your gut: symptoms include severe stomach pain, vomiting, fever, or chills.
  • severe bleeding in your gut: symptoms may include extreme tiredness, weakness, dizziness or changes in the colour of your stools.
  • Abnormal tube-like connections or passageways inside the body (fistula): symptoms will depend on the location of the fistula, but may include diarrhoea, infection of the urine (burning with urination, cloudy or bloody urine), pain in the abdominal area.
Blood vessel related:
  • blood clots in the arteries can lead to a heart attack or stroke. Symptoms of a heart attack may include chest pain or heaviness in the chest. Symptoms of a stroke may include sudden numbness or weakness of the arm, leg and face, feeling confused, difficulty speaking or understanding others, sudden difficulty in walking or loss of balance or coordination, memory loss, blurred or loss of vision or sudden dizziness.
  • an enlargement and weakening of a blood vessel wall (aneurysm): symptoms may include sudden and severe pain in the abdomen or back.
  • tear in a blood vessel wall (artery dissections): symtoms may include sudden, severe abdominal, chest, or back pain.
Allergic reaction related:
  • infusion-related reactions: symptoms may include increased muscle tension, tremors, back pain and/or spasms, chest pain and/or tightness, chills, flushing, difficulty breathing, wheezing, and feeling of tingling or numbness in the hands or feet. In severe cases, symptoms may include breathing distress caused by narrowing of the airways, faster heartbeat, and feeling faint.
  • sudden signs of allergy: rash, itching or hives on the skin, swelling of the face, lips or tongue or other parts of the body, shortness of breath, wheezing or trouble breathing.
Head related:
  • a brain condition called posterior reversible encephalopathy syndrome (PRES): symptoms may include fits (seizures), headache, feeling sick (nausea), vomiting, loss of vision or reduced alertness, with or without high 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.
CYRAMZA may be permanently stopped if you develop any of these 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 CYRAMZA contains

Active ingredient
(main ingredient)
ramucirumab
Other ingredients
(inactive ingredients)
glycine
histidine
histadine hydrochloride monohydrate
polysorbate 80
sodium chloride
water for injections

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

What CYRAMZA looks like

CYRAMZA is a clear to slightly opalescent and colourless to slightly yellow solution and is available in a glass vial container with a rubber stopper.

CYRAMZA is available in packs of:

  • 1 vial of 10 mL
  • 1 vial of 50 mL

Australian Registration Numbers:
CYRAMZA 100 mg, AUST R 227351
CYRAMZA 500 mg, AUST R 227352

Not all packs may be marketed.

Who distributes CYRAMZA

CYRAMZA is supplied in Australia by:

Eli Lilly Australia Pty Limited
112 Wharf Road
WEST RYDE NSW 2114

This leaflet was prepared in April 2021

®Registered Trademark

Published by MIMS May 2021

BRAND INFORMATION

Brand name

Cyramza

Active ingredient

Ramucirumab

Schedule

S4

 

1 Name of Medicine

Ramucirumab [rmc].

2 Qualitative and Quantitative Composition

Cyramza is available as a concentrate in 10 mL or 50 mL single-use vials. Each vial contains either 100 mg ramucirumab in 10 mL (10 mg/mL) or 500 mg ramucirumab in 50 mL (10 mg/mL). Cyramza contains the excipients histidine, histidine hydrochloride monohydrate, glycine, sodium chloride, polysorbate 80 and water for injections.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for intravenous infusion vial.
Cyramza is a sterile, clear to slightly opalescent and colourless to slightly yellow solution without visible particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Cyramza, in combination with paclitaxel, is indicated for the treatment of adult patients with advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum and fluoropyrimidine chemotherapy.
Cyramza, as monotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum or fluoropyrimidine chemotherapy when treatment in combination with paclitaxel is not appropriate.

4.2 Dose and Method of Administration

General.

Do not administer ramucirumab as an intravenous push or bolus.
After dilution and preparation, Cyramza is administered as an intravenous infusion.
Only use sterile sodium chloride (0.9%) solution for injection as a diluent. Do not use dextrose as a diluent.
It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.

Premedication.

Premedication is recommended with a histamine H1 antagonist (e.g. promethazine) intravenously prior to administration of ramucirumab.
If a patient experiences a grade 1 or 2 infusion related reaction (IRR), premedication must be given for all subsequent infusions. If a patient has a second grade 1 or 2 IRR, administer dexamethasone (or equivalent); then, for subsequent infusions, premedicate with the following or equivalent medications: promethazine hydrochloride (intravenously), paracetamol, and dexamethasone (see Section 4.2 Dose and Method of Administration, Dose or infusion rate adjustments).

Gastric adenocarcinoma.

Ramucirumab in combination with paclitaxel.

The recommended dose of ramucirumab is 8 mg/kg on days 1 and 15 of a 28 day cycle, prior to paclitaxel infusion. The recommended dose of paclitaxel is 80 mg/m2 administered by intravenous infusion over approximately 60 minutes on days 1, 8 and 15 of a 28 day cycle. Prior to each paclitaxel infusion, patients should have a complete blood count and blood chemistry performed to evaluate hepatic function. Criteria to be met prior to each paclitaxel administration are provided in Table 1.

Ramucirumab single agent.

The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks administered as an intravenous infusion over approximately 60 minutes (maximum infusion rate 25 mg/min).

Dose or infusion rate adjustments.

Infusion related reactions.

Reduce the ramucirumab infusion rate by 50% for the duration of the infusion and all subsequent infusions if the patient experiences a grade 1 or 2 IRR (per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (see Section 4.2 Dose and Method of Administration, Premedication). Immediately and permanently discontinue ramucirumab for grade 3 or 4 IRRs (see Section 4.4 Special Warnings and Precautions for Use).

Hypertension.

Monitor blood pressure during treatment with ramucirumab and treat as clinically indicated. Temporarily suspend ramucirumab for severe hypertension until controlled with medical management (see Section 4.4 Special Warnings and Precautions for Use).

Posterior reversible encephalopathy syndrome.

Permanently discontinue ramucirumab in patients who experience posterior reversible encephalopathy syndrome (PRES) (see Section 4.4 Special Warnings and Precautions for Use).

Proteinuria.

Monitor for the development or worsening of proteinuria during ramucirumab therapy. If the urine protein level is ≥ 2+, perform a 24 hour urine collection. Temporarily discontinue ramucirumab administration if the urine protein level is ≥ 2 g/24 hours. Resume treatment at a reduced dose level (to 6 mg/kg every two weeks) once the urine protein level returns to < 2 g/24 hours. A second dose reduction to 5 mg/kg every two weeks) is recommended if a urine protein level ≥ 2 g/24 hours reoccurs.
Permanently discontinue ramucirumab therapy if the urine protein level is > 3 g/24 hours or in the setting of nephrotic syndrome (see Section 4.8 Adverse Effects (Undesirable Effects)).

Paclitaxel.

Paclitaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient. For NCI-CTCAE grade 4 haematological toxicity or grade 3 paclitaxel related non-haematological toxicity, it is recommended to reduce the paclitaxel dose by 10 mg/m2 for all following cycles. A second reduction of 10 mg/m2 is recommended if these toxicities persist or reoccur. See paclitaxel prescribing information for additional dosage and administration recommendations.
See paclitaxel prescribing information for premedication requirements.

Impaired wound healing.

Ramucirumab therapy should be temporarily discontinued for at least 4 weeks prior to elective surgery. Ramucirumab therapy should be temporarily discontinued if there are wound healing complications, until the wound is fully healed (see Section 4.4 Special Warnings and Precautions for Use).

Permanently discontinue ramucirumab therapy in the event of.

Severe arterial thromboembolic events, gastrointestinal perforations, NCI CTCAE grade 3 or 4 bleeding (see Section 4.4 Special Warnings and Precautions for Use).

Fistula.

Ramucirumab therapy should be permanently discontinued in the event of spontaneous development of fistula (see Section 4.4 Special Warnings and Precautions for Use).

Use in renal impairment.

There have been no formal studies with ramucirumab in patients with renal impairment. No dose reductions are recommended.

Use in hepatic impairment.

There have been no formal studies with ramucirumab in patients with hepatic impairment. No dose reductions are recommended (see Section 4.4 Special Warnings and Precautions for Use).

Instructions for use/handling.

Do not administer or mix with dextrose solution.
1. Prepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution.
2. Each vial is intended for use in one patient on one occasion only and discard any residue. Inspect the content of the vials prior to dilution for particulate matter and discolouration (see Section 3 Pharmaceutical Form). If particulate matter or discolourations are identified, discard the vial.
3. Calculate the dose and volume of ramucirumab needed to prepare the infusion solution. Vials contain either 100 mg or 500 mg as a 10 mg/mL concentrate of ramucirumab. Dilute ramucirumab as required to achieve a final volume of 250 mL. Only use sterile sodium chloride (0.9%) solution for injection as a diluent.

In case of prefilled intravenous infusion container usage.

Based on the calculated volume of ramucirumab, remove the corresponding volume of sterile sodium chloride (0.9%) solution for injection from the prefilled 250 mL intravenous container. Aseptically transfer the calculated volume of ramucirumab to the intravenous container. The final volume in the container should be 250 mL. The container should be gently inverted to ensure adequate mixing. Do not freeze or shake the infusion solution. Do not dilute with other solutions or co-infuse with other electrolytes or medications.

In case of empty intravenous infusion container usage.

Aseptically transfer the calculated volume of ramucirumab into an empty intravenous container. Add a sufficient quantity of sterile sodium chloride (0.9%) solution for injection to the container to make the total volume 250 mL. The container should be gently inverted to ensure adequate mixing. Do not freeze or shake the infusion solution. Do not dilute with other solutions or co-infuse with other electrolytes or medication.
4. Parenteral drug products should be inspected visually for particulate matter prior to administration. If particulate matter is identified, discard the infusion solution.
5. Discard any unused portion of ramucirumab left in a vial, as the product contains no preservatives.
Administer via infusion pump. A separate line with a protein sparing 0.22 micron filter must be used for the infusion and the line must be flushed with sterile sodium chloride (0.9%) solution for injection at the end of the infusion.

4.3 Contraindications

Cyramza is contraindicated in patients with known hypersensitivity to ramucirumab or to any of the excipients in the product.

4.4 Special Warnings and Precautions for Use

Neutropenia.

Severe neutropenia has been reported in clinical trials with ramucirumab in combination with chemotherapy. Blood counts should be monitored in patients receiving ramucirumab in combination with chemotherapy.

Arterial thromboembolic events.

Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischaemia have been reported in clinical trials. Permanently discontinue ramucirumab in patients who experience a severe ATE (see Section 4.2 Dose and Method of Administration).

Hypertension.

An increased incidence of severe hypertension was observed in clinical trials. Patients with uncontrolled hypertension were excluded from the clinical trials and ramucirumab should not be commenced until their hypertension is controlled. Monitor blood pressure regularly, and withhold ramucirumab for patients who develop hypertension until it is adequately controlled. In clinical trials, hypertension was controlled in most instances with standard antihypertensives. Permanently discontinue ramucirumab if medically significant hypertension cannot be controlled with antihypertensive therapy (see Section 5.2 Pharmacokinetic Properties).

Aneurysms and artery dissections.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating ramucirumab, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Gastrointestinal perforations.

Cases, sometimes fatal, of gastrointestinal perforation have been reported in patients treated with ramucirumab. Permanently discontinue ramucirumab in patients who experience gastrointestinal perforations (see Section 4.2 Dose and Method of Administration).

Severe bleeding.

Severe gastrointestinal haemorrhage including fatal events were reported in patients with gastric adenocarcinoma treated with ramucirumab in combination with paclitaxel.
Ramucirumab is an antiangiogenic therapy and has the potential to increase the risk of severe bleeding. Ramucirumab should be permanently discontinued in patients who experience grade 3 or 4 bleeding (see Section 4.2 Dose and Method of Administration). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants or other concomitant medicinal products that increase the risk of bleeding.

Infusion related reactions.

Infusion related reactions (IRR) were reported in clinical trials with ramucirumab. The majority of events occurred during or following a first or second ramucirumab infusion. Monitor patients during the infusion for signs of hypersensitivity reactions with resuscitation equipment readily available. Symptoms included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnoea, wheezing, hypoxia, and paraesthesia. In severe cases symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Immediately and permanently discontinue ramucirumab for grade 3 or 4 IRRs (see Section 4.2 Dose and Method of Administration).

Impaired wound healing.

The impact of ramucirumab has not been evaluated in patients with serious or non-healing wounds. In a study conducted in animals, ramucirumab did not impair wound healing in monkeys. However, since ramucirumab is an antiangiogenic therapy and may have the potential to adversely affect wound healing, ramucirumab treatment should be withheld for at least 4 weeks prior to scheduled surgery. The decision to resume ramucirumab following surgical intervention should be based on clinical judgement of adequate wound healing.
If a patient develops wound healing complications during therapy, discontinue ramucirumab until the wound is fully healed (see Section 4.2 Dose and Method of Administration).

Posterior reversible encephalopathy syndrome (PRES)/ reversible posterior leukoencephalopathy syndrome (RPLS).

Cases of PRES, including fatal cases, have been rarely reported in patients receiving ramucirumab.
PRES (or RPLS) has been reported with a rate of < 0.1% in clinical studies and in the postmarket setting with ramucirumab (see Section 4.8 Adverse Effects (Undesirable Effects)). PRES is a neurological disorder which can present with seizures, headache, nausea/vomiting, hypertension, seizure, lethargy, confusion, blindness and other visual and neurological disturbances, and can be fatal.
Confirm the diagnosis of PRES with MRI and discontinue ramucirumab in patients who develop PRES. Permanently discontinue ramucirumab in patients who experience PRES.

Fistula.

Patients may be at increased risk for the development of fistula when treated with ramucirumab. Ramucirumab treatment should be discontinued in patients who develop fistula (see Section 4.2 Dose and Method of Administration).

Use in hepatic impairment.

Ramucirumab should be used with caution in patients with severe liver cirrhosis (Child-Pugh B or C), cirrhosis with hepatic encephalopathy, clinically significant ascites due to cirrhosis, or hepatorenal syndrome. In these patients, ramucirumab should only be used if the potential benefits of treatment are judged to outweigh the potential risk of progressive hepatic failure (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

There are no safety data available for patients with severe renal impairment (eGFR < 30 mL/min) treated with ramucirumab (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

In the REGARD and RAINBOW studies there has been no indication that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No reduction in starting dose is recommended.

Paediatric use.

The safety and effectiveness of ramucirumab has not been established in patients under 18 years of age.
In cynomolgus monkeys that received 5-50 mg/kg IV ramucirumab weekly for 39 weeks, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested. At the lowest dose the relative exposure in monkeys was less than the anticipated clinical exposure based on AUC.

Effects on laboratory tests.

Changes in laboratory test parameters (including hyponatraemia, hypokalaemia, liver function disturbances and myelosuppression) may occur with ramucirumab therapy as a single agent or in combination with chemotherapy. Electrolyte, liver function tests and a full blood count should be monitored, including during monotherapy (also see Neutropenia, Use in hepatic impairment).

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug-drug interactions were observed between ramucirumab and paclitaxel. The pharmacokinetics (PK) of paclitaxel was not affected when coadministered with ramucirumab and the PK of ramucirumab was not affected when coadministered with paclitaxel.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproductive toxicity studies with ramucirumab have not been performed, however, animal models link angiogenesis, VEGF and VEGF receptor 2 to critical aspects of female reproduction. Based on ramucirumab's mechanism of action, it is likely that ramucirumab will inhibit angiogenesis and result in adverse effects on fertility, including impaired ovulation, endometrial and placental function, and corpus luteum development. Treatment related increases in follicular mineralisation of the ovary were also observed in monkeys that received ramucirumab weekly for 39 weeks at clinically relevant exposures.
There are no data on the effect of ramucirumab on human fertility. Female fertility is likely to be compromised during treatment with ramucirumab based on studies in animals.
(Category D)
There are no adequate or well controlled studies of the use of ramucirumab in pregnant women or animals. IgG antibodies cross the placental barrier and ramucirumab may therefore inhibit angiogenesis in the developing foetus. As angiogenesis is critical to maintenance of pregnancy and to foetal development, this inhibition of angiogenesis may result in adverse effects on pregnancy, including foetal death and impaired heart, lung and kidney development. Ramucirumab is not recommended during pregnancy, and women of childbearing potential should be advised to use effective contraception. Women of childbearing potential or women who become pregnant during treatment should be counselled as to the potential risks of ramucirumab to the foetus and for maintaining pregnancy. Based on the half-life of ramucirumab, women of childbearing potential should be advised to avoid becoming pregnant while receiving ramucirumab and for at least 3 months after the last dose of ramucirumab.
It is unknown whether ramucirumab is excreted in human milk. Excretion in milk and oral absorption is expected to be low. As a risk to newborns/infants cannot be excluded, breastfeeding should be discontinued during treatment with ramucirumab and for at least 3 months after the last dose.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on ability to drive or use machinery have been performed. If patients experience treatment related symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

4.8 Adverse Effects (Undesirable Effects)

Ramucirumab in combination with paclitaxel for gastric adenocarcinoma.

Table 2 provides the frequency and severity of adverse drug reactions (ADRs) reported in ≥ 5% of ramucirumab treated patients in RAINBOW, a phase 3 gastric adenocarcinoma study of ramucirumab in combination with paclitaxel. Frequency of adverse drug reactions: very common ≥ 10%. Refer to NCI CTCAE Criteria (Version 4.0) for each grade of toxicity.
Clinically relevant ADRs reported in ≥ 1% and < 5% of the ramucirumab plus paclitaxel treated patients in RAINBOW were gastrointestinal perforation (1.2% ramucirumab plus paclitaxel versus 0.3% for placebo plus paclitaxel) and sepsis (3.1% ramucirumab plus paclitaxel versus 1.8% placebo plus paclitaxel).

Single agent ramucirumab for gastric adenocarcinoma.

Table 3 provides the frequency and severity of adverse drug reactions (ADRs) reported in ≥ 5% of ramucirumab treated patients in REGARD, a single agent, placebo controlled phase 3 gastric adenocarcinoma study.
Frequency of adverse drug reactions: very common ≥ 10%; common ≥ 1% and < 10%. Refer to NCI CTCAE Criteria (Version 4.0) for each grade of toxicity.
Clinically relevant ADRs reported in ≥ 1% and < 5% of the ramucirumab treated patients in REGARD were: neutropenia, arterial thromboembolic events, intestinal obstruction, epistaxis, and rash.
Clinically relevant reactions (including grade ≥ 3) associated with antiangiogenic therapy observed in ramucirumab treated patients across clinical trials were proteinuria, infusion related reactions, and gastrointestinal perforations (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Postmarketing experience.

Nervous system disorders.

Rare (< 0.1% and > 0.01%): posterior reversible encephalopathy syndrome/ reversible posterior leukoencephalopathy syndrome.
Spontaneous data. The following adverse drug reactions are based on postmarketing reports.

Blood and lymphatic system disorders.

Thrombotic microangiopathy: Rare (≥ 0.01% - < 0.1%).

Neoplasms benign, malignant and unspecified.

Haemangioma: Common (≥ 1.0% - < 10%).

Nervous system disorders.

Posterior reversible encephalopathy syndrome: Rare (≥ 0.01% - < 0.1%) (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Respiratory, thoracic and mediastinal disorders.

Dysphonia: Common (≥ 1.0% - < 10%).

Endocrine disorders.

Hypothyroidism: Common (≥ 1.0% - < 10%).

Vasular disorders.

Cases of aneurysms and artery dissections, sometimes fatal, have been reported with VEGFR pathway inhibitors.

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

There is no data on overdose in humans. Ramucirumab has been administered in a phase 1 study up to 10 mg/kg every two weeks without reaching a maximum tolerated dose. In case of overdose, use supportive therapy. There is no known antidote to ramucirumab overdose.
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.

VEGF receptor 2 is the key mediator of VEGF induced angiogenesis. Ramucirumab is a human receptor targeted antibody that specifically binds VEGF receptor 2 and blocks binding of VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand stimulated activation of VEGF receptor 2 and its downstream signalling components including p44/p42 mitogen activated protein kinases, neutralising ligand induced proliferation and migration of human endothelial cells.

Immunogenicity.

Overall, there was a low incidence of both treatment emergent anti-drug antibodies and neutralising antibodies among ramucirumab treated patients, and no correlation with safety outcomes in these patients. There was no relationship between immunogenicity and infusion related reactions (IRRs) or treatment emergent adverse events. There is insufficient data to evaluate the effects of anti-drug antibodies (ADAs) on the efficacy or safety of ramucirumab.

Clinical trials.

RAINBOW. RAINBOW, a multinational, randomised, double blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel, was conducted in 665 patients with locally advanced or metastatic gastric adenocarcinoma (including adenocarcinoma of the gastro-oesophageal junction (GEJ)) following platinum or fluoropyrimidine containing chemotherapy with or without anthracycline. The primary endpoint was overall survival (OS) and secondary endpoints included progression free survival (PFS) and overall response rate (ORR). Patients were required to have experienced disease progression during, or within 4 months after the last dose of first line therapy with ECOG performance status (PS) 0-1.
Patients were randomised in a 1:1 ratio to receive ramucirumab plus paclitaxel (n = 330) or placebo plus paclitaxel (n = 335). Randomisation was stratified by geographic region, time to progression from the start of first line therapy (< 6 months versus ≥ 6 months) and disease measurability. Ramucirumab at 8 mg/kg or placebo was administered by intravenous infusion every 2 weeks (on days 1 and 15) of a 28 day cycle. Paclitaxel at 80 mg/m2 was administered by intravenous infusion on days 1, 8 and 15 of each 28 day cycle.
A majority (75%) of patients randomised in the study received prior platinum/fluoropyrimidine combination therapy without an anthracycline. The remainder (25%) received prior platinum/fluoropyrimidine combination therapy with an anthracycline. Two-thirds of the patients experienced disease progression while still on first line therapy (66.8%). Baseline patient demographics and disease characteristics were generally balanced between the study arms. The median age was 61 years; 71% of the patients were male; 61% were Caucasian, 35% Asian; the ECOG PS was 0 for 39% of patients, 1 for 61% of patients; 81% of patients had measurable disease and 79% had gastric adenocarcinoma; 21% had GEJ adenocarcinoma. The majority of patients (76%) had experienced disease progression within 6 months from the start of first line therapy.
For patients treated with ramucirumab plus paclitaxel the median duration of therapy was 19 weeks, and for patients treated with placebo plus paclitaxel the median duration of therapy was 12 weeks. The median relative dose intensity of ramucirumab was 98.6% and of placebo was 99.6%. The median relative dose intensity of paclitaxel was 87.7% for the ramucirumab plus paclitaxel arm and 93.2% for the placebo plus paclitaxel arm. A similar percentage of patients discontinued treatment due to adverse events: 12% of patients treated with ramucirumab plus paclitaxel compared with 11% of patients treated with placebo plus paclitaxel. Postdiscontinuation systemic anticancer therapy was given to 47.9% of patients receiving ramucirumab plus paclitaxel and 46.0% of patients receiving placebo plus paclitaxel.
Table 4 shows efficacy outcomes on overall survival (OS), progression free survival (PFS) and objective response rate (ORR).

Eastern cooperative oncology group (ECOG) performance status (PS) ≥ 2 patients.

Patients with ECOG score ≥ 2 were excluded from the pivotal studies, therefore the safety and efficacy of Cyramza in this patient population is unknown. See Figures 1 and 2.
REGARD. REGARD, a multinational, randomised, double blind, multicentre study of ramucirumab plus best supportive care (BSC) versus placebo plus BSC, was conducted in 355 patients with locally advanced or metastatic gastric adenocarcinoma (including adenocarcinoma of the gastro-oesophageal junction (GEJ)) following platinum or fluoropyrimidine containing chemotherapy. The primary endpoint was overall survival (OS) and secondary endpoints included progression free survival (PFS) and 12 week PFS rate. Patients were required to have experienced disease progression during first line treatment or within 4 months after the last dose of first line therapy for metastatic disease, or during adjuvant treatment or within 6 months after the last dose of adjuvant therapy, and had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. Patients were randomised in a 2:1 ratio to receive an intravenous infusion of ramucirumab 8 mg/kg (n = 238) or placebo (n = 117) every 2 weeks. Randomisation was stratified by weight loss over the prior 3 months (≥ 10% versus < 10%), geographic region, and location of the primary tumour (gastric versus GEJ).
Patients enrolled in the study received prior platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine containing regimens without platinum (15%), or platinum containing regimens without fluoropyrimidine (4%). With respect to baseline demographics and disease characteristics: the median age was 60 years; 70% of patients were male; 77% were Caucasian, 16% Asian; the ECOG PS was 0 for 28% of patients and 1 for 72% of patients; 91% of patients had measurable disease; and 75% of patients had gastric adenocarcinoma, 25% adenocarcinoma of the GEJ. The majority of patients (85%) had experienced disease progression during first line treatment or following first line therapy and the remainder during or following adjuvant therapy. Patients received a median of 4 cycles (range 1-34) of ramucirumab and 3 cycles (range 1-30) of placebo.
The median relative dose intensity of ramucirumab was 99.6%. Eleven percent of patients treated with ramucirumab and 6% of patients on placebo discontinued therapy due to adverse events. Overall survival was statistically significantly improved in patients receiving ramucirumab as compared with patients receiving placebo (hazard ratio (HR) 0.776; 95% CI: 0.603 to 0.998; p = 0.0473), corresponding to a 22% reduction in the risk of death and an increase in median survival to 5.2 months for ramucirumab from 3.8 months for placebo. Progression free survival was statically significantly improved in patients receiving ramucirumab as compared with patients receiving placebo (HR 0.483; 95% CI: 0.376 to 0.620; p < 0.0001), corresponding to a 52% reduction in the risk of progression or death and an increase in median PFS to 2.1 months for ramucirumab from 1.3 months for placebo. Efficacy results are shown in Table 5.

Eastern cooperative oncology group (ECOG) performance status (PS) ≥ 2 patients.

Patients with ECOG score ≥ 2 were excluded from the pivotal studies, therefore the safety and efficacy of Cyramza in this patient population is unknown. See Figures 3 and 4.

5.2 Pharmacokinetic Properties

Absorption.

Ramucirumab is administered as an intravenous infusion. There have been no studies performed with other routes of administration.

Distribution.

Following the dose regimen of 8 mg/kg ramucirumab (single agent) every 2 weeks, the geometric means of ramucirumab Cmin were 49.5 microgram/mL (range of 6.3-228 microgram/mL) and 74.4 microgram/mL (range of 13.8-234 microgram/mL) prior to administration of the fourth and seventh dose, respectively, in serum from patients with advanced gastric adenocarcinoma. Based on population pharmacokinetic approach (PopPK), the mean volume of distribution at steady state for ramucirumab was 5.5 L for gastric adenocarcinoma patients.

Metabolism.

The metabolism of ramucirumab has not been studied. Antibodies are principally cleared by catabolism.

Excretion.

Based on PopPK, the mean clearance of ramucirumab was 0.014 L/hr and the mean half-life was 15 days for gastric adenocarcinoma patients.

Special populations.

PopPK analysis suggested age, gender, bodyweight, and race had no effect on the PK of ramucirumab.

Elderly patients.

Based on the results of the PopPK analysis, there was no difference in ramucirumab exposure in patients ≥ 65 years of age compared to patients < 65 years old.

Renally impaired patients.

No formal studies have been conducted to evaluate the effect of renal impairment on the PK of ramucirumab. Based on the results of the PopPK analysis, ramucirumab exposure was similar in patients with mild renal impairment (calculated creatinine clearance (CrCl) ≥ 60 to < 90 mL/min) and moderate renal impairment (CrCl ≥ 30 to < 60 mL/min) as to patients with normal renal function (CrCl ≥ 90 mL/min). No data were available from patients with severe renal impairment (CrCl < 30 mL/min).

Hepatically impaired patients.

No formal studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab.

Exposure response relationships: RAINBOW.

Exposure response analyses indicated that efficacy and specific measures of safety of ramucirumab were correlated with ramucirumab exposure. Increased efficacy, as measured by improvements in OS and PFS, was associated with increasing ramucirumab exposure range which was produced by 8 mg/kg ramucirumab given on days 1 and 15 of a 28 day cycle. The incidences of grade ≥ 3 hypertension, neutropenia, and leucopenia were also increased with higher ramucirumab exposure (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Exposure response relationship: REGARD.

Based on limited PK data, exposure response analysis suggested that efficacy of ramucirumab was correlated with ramucirumab exposure.

5.3 Preclinical Safety Data

Genotoxicity.

No animal studies have been performed to test ramucirumab for potential genotoxicity.

Carcinogenicity.

No animal studies have been performed to test ramucirumab for potential carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Do not administer or mix with dextrose solution.

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

Cyramza should be stored in a refrigerator between 2 to 8°C. Do not freeze. Do not shake the vial.
Keep the vial in the outer carton in order to protect from light.
Chemical and physical in-use stability of Cyramza in sodium chloride 9 mg/mL (0.9%) solution for injection has been demonstrated for: 24 hours at 2 to 8°C or for 4 hours at 25°C. Do not freeze or shake the infusion solution.

6.5 Nature and Contents of Container

Cyramza is available as 10 mL and 50 mL concentrates in a vial (type I glass) with a chlorobutyl rubber stopper, an aluminium seal and polypropylene cap.
Cyramza is available in packs* of 1 of 10 mL and 1 vial of 50 mL.
*Not all pack sizes may be marketed.

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

Chemical structure.

Ramucirumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology.
Ramucirumab is a human monoclonal antibody composed of 2 heavy chain (γ1-chain) molecules consisting of 446 amino acid residues each and 2 light chain (κ-chain) molecules consisting of 214 amino acid residues each.
The average molecular mass of ramucirumab with the predominant form of N-linked glycosylation is 146,756 Da.

CAS number.

947687-13-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Medicine.

Summary Table of Changes