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.

What is in this leaflet

This leaflet answers some common questions about CYRAMZA. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking CYRAMZA against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

The information in this leaflet was last updated on the date shown on the final page. More recent information on this medicine may be available. Make sure you speak to your pharmacist, nurse or doctor to obtain the most up to date information on this medicine. You can also download the most up to date leaflet from www.lilly.com.au. The updated leaflet may contain important information about CYRAMZA and its use that you should be aware of.

What CYRAMZA is used for

CYRAMZA contains the active ingredient ramucirumab.

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

It 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.

Your doctor may have prescribed it for another reason.

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

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

CYRAMZA may be used in combination with other chemotherapy drugs.

Before you are given CYRAMZA

When you must not be given it

Do not take CYRAMZA if you have an allergy to:

  • any medicine containing ramucirumab
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have or have had any of the following medical conditions:

  • any condition which increases the risk of bleeding, or you are taking any medicines which may increase the risk of bleeding or which affect blood clotting ability.
  • high blood pressure. Your doctor will make sure that your blood pressure is brought under control before starting CYRAMZA.
  • severe liver disease ('cirrhosis') and associated conditions, such as excessive accumulation of fluid in your abdomen ('ascites').
  • are going to have planned surgery, if you have had recent surgery or if you have a poorly healing wound after surgery. CYRAMZA may increase the risk of problems with wound healing. You should not receive CYRAMZA for at least 4 weeks before you undergo planned surgery and your doctor will decide when to start treatment.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Pregnancy and breast-feeding 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.

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.

If you have not told your doctor about any of the above, tell him/her before you take CYRAMZA.

Taking Premedication

Your doctor may advise you to take certain medicines to reduce the risk of an infusion-related reaction before you receive CYRAMZA.

If you experience an infusion-related reaction during CYRAMZA therapy, you will be given premedication for all future infusion.

Ask your doctor if you have any questions about why these other medicines have been prescribed for you.

Taking other medicines

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

Some medicines maybe affected by CYRAMZA.

You may need different amounts of your medicines or to stop taking them for a few days. Or you may need to take different medicines.

How CYRAMZA will be given

Follow all directions given to you by your doctor or pharmacist carefully.

How much is given

Your doctor will decide the dosage of CYRAMZA you should take. This will depend on your body 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.

If you experience an infusion-related reaction during treatment, the time taken to give your infusion will be increased for the duration of that infusion and all future infusions.

Your doctor or nurse will inject CYRAMZA for you.

Never inject CYRAMZA yourself. Always let your doctor or nurse do this.

How often it is given

CYRAMZA is given once every two weeks as part of the treatment cycle. Your doctor will advise how many treatment cycles you need.

CYRAMZA treatment will be temporarily stopped if you:

  • develop severe high blood pressure, until it is controlled with anti-hypertensive medication
  • develop wound healing problems, until the wound is healed or prior to planned surgery.

The amount of protein in your urine will be checked regularly during treatment. Your doctor may decide to change your dose or delay treating you depending on your general condition and if your urine protein levels are too high. Once your urine protein level has decreased to a certain level, treatment may be restarted with a lower dose.

CYRAMZA treatment will be permanently stopped if you:

  • develop a blood clot in your arteries
  • develop a hole in your gut wall
  • experience severe bleeding
  • experience a severe infusion-related reaction
  • develop high blood pressure that cannot be controlled with medication
  • are passing more than a certain amount of protein with your urine or if you develop a severe kidney disease (nephrotic syndrome)
  • notice any changes in your movement or behaviour
  • develop abnormal tube-like connections or passageways inside the body between internal organs and skin or other tissues

Overdose

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

While you are receiving CYRAMZA

Things you must do

Talk to your doctor or nurse immediately if any of the following applies to you (or you are not sure) during treatment with CYRAMZA or thereafter:

  • blocking of the arteries by a blood clot. CYRAMZA can cause blood clots in your arteries. Arterial blood clots can lead to serious conditions, including 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, or sudden dizziness. CYRAMZA will be permanently stopped if you develop a blood clot in your arteries.
  • holes in your gut wall. CYRAMZA has the potential to increase the risk of holes in your gut wall. Symptoms may include severe abdominal pain, being sick (vomiting), fever or chills. CYRAMZA will be permanently stopped if you develop a hole in your gut wall.
  • severe bleeding. CYRAMZA has the potential to cause severe bleeding. Symptoms may include extreme tiredness, weakness, dizziness or changes in the colour of your stools. CYRAMZA will be permanently stopped if you experience severe bleeding.
  • infusion-related reactions. Infusion-related reactions may happen with treatment with CYRAMZA. Your doctor or nurse will check for side effects during your infusion. Symptoms may include increased muscle tension and/or 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. CYRAMZA will be permanently stopped if you experience a severe infusion-related reaction.
  • abnormal tube-like connections or passageways inside the body. CYRAMZA may increase the risk of abnormal tube-like connections or passageways inside the body between internal organs and skin or other tissues. Cyramza will be permanently stopped if you develop fistulae.

Tell your partner or caregiver you are receiving CYRAMZA and ask them to tell you if they notice any changes in your movement or behaviour. If they notice any changes you should tell your doctor about them immediately.

Talk to your doctor about regular blood pressure monitoring. CYRAMZA may cause high blood pressure. Most people have no symptoms from this. Talk to your doctor about measuring your blood pressure. CYRAMZA will be permanently stopped if you develop high blood pressure that cannot be managed with medication.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are receiving CYRAMZA.

Tell any other doctors, dentists and pharmacists who treat you that you are receiving this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are receiving this medicine. It may increase the risk of problems with wound healing. You should not receive CYRAMZA before you undergo planned surgery and your doctor will decide when to re-start treatment.

If you become pregnant while receiving this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are receiving this medicine.

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.

Things to be careful of

Be careful driving or operating machinery 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 affecting your ability to concentrate and react, do not drive, operate or do anything else that could be dangerous until the effect goes away.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking CYRAMZA.

This medicine is to help people with gastric cancer, including cancers of the junction between the oesophagus and the stomach, but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Because CYRAMZA may be used with other medicines that treat cancer, it may be difficult for your doctor to tell whether the side effects are due to CYRAMZA or due to other medicines.

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

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • feeling tired or weak
  • diarrhoea
  • nose bleed
  • abdominal pain
  • intestinal blockage; symptoms may include constipation and abdominal pain
  • swelling of the hands, feet and legs due to fluid retention
  • high blood pressure
  • inflammation of the mouth
  • headache
  • muscle weakness or twitching
  • abnormal heart rhythm
  • confusion
  • bleeding or bruising more easily than normal
  • 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.
  • Changes in speech

The above lists include the more common side effects of your medicine. When used in combination with other chemotherapy medicine, also refer to the other product's consumer medicine information leaflet for a list of other possible side effects.

Tell your doctor as soon as possible if you notice any of the following:

  • fever or infection with a temperature, sweating or other signs of infection
  • severe abdominal pain
  • being sick (vomiting)
  • extreme tiredness, weakness or dizziness
  • changes in the colour of your stools.

The above list includes serious side effects which may require medical attention.

If any of the following happen, tell your doctor immediately or go to the Emergency Department at your nearest hospital:

  • signs of a heart attack such as chest pain or heaviness in the chest
  • signs of a stroke such as 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, or sudden dizziness
  • sudden signs of allergy such as 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.
  • vision loss associated with headaches, confusion and seizures
  • one or a combination of the following: confusion, disorientation or memory loss, changes in the way you move, walk or talk, decreased strength or progressive weakness in your body, blurred or loss of vision.

The above list includes very serious side effects and can be life-threatening. You may need urgent medical attention or hospitalisation. Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people. Some of these side effects (for example, abnormal blood tests showing low cell counts, low blood levels of albumin, potassium or sodium, or urine tests showing high protein levels) can only be found when your doctor does tests to check your progress.

This is not a complete list of all possible side effects. Others may occur in some people and there may be some side effects not yet known.

After receiving CYRAMZA

Storage

This medicine will be stored in the hospital pharmacy or on the ward.

It will be kept in a refrigerator at a temperature between 2°C and 8°C in the outer carton to protect from light.

Disposal

CYRAMZA is for single use only.

The vials should be used once only and any remaining contents should be discarded.

Product description

What it 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.

Not all pack sizes may be marketed.

Ingredients

CYRAMZA is supplied in 10 mL and 50 mL vials.

The 10 mL vial of CYRAMZA contains 100 mg of ramucirumab, 6.5 mg of histidine, 12.2 mg of histidine hydrochloride monohydrate, 99.8 mg of glycine, 43.8 mg of sodium chloride, 1 mg of polysorbate 80 and water for injections to 10mL.

The 50 mL vial of CYRAMZA contains 500 mg of ramucirumab, 32.5 mg of histidine, 61 mg of histidine hydrochloride monohydrate, 499 mg of glycine, 219 mg of sodium chloride, 5 mg of polysorbate 80 and water for injections to 50mL.

Supplier

CYRAMZA is supplied in Australia by:

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

Australian Registration Numbers:

CYRAMZA 100 mg, AUST R 227351

CYRAMZA 500 mg, AUST R 227352

This leaflet was prepared in April 2020.

®= Registered Trademark

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Cyramza

Active ingredient

Ramucirumab

Schedule

S4

 

1 Name of Medicine

Ramucirumab [rmc].

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.

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.

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 antidrug 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.

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.

4.3 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).

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).

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).

Impaired wound healing.

The impact of ramucirumab has not been evaluated in patients with serious or nonhealing 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.

4.8 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%).

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.

4.2 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 nonhaematological 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 coinfuse 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 coinfuse 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.

4.7 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.

4.9 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).

7 Medicine Schedule (Poisons Standard)

S4.

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.

Summary Table of Changes