PACL(W)+RAMU

REPEAT EVERY 28 DAYS

Until disease progression or unacceptable toxicity occurs

If paclitaxel is later discontinued due to toxicity or intolerance, may continue with single agent ramucirumab until disease progression

• Also refer to CCO Antiemetic Recommendations.
   

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
 

Premedications (prophylaxis for infusion reactions):

On days 1 and 15:*

• diphenhydramine 25-50mg IV (or equivalent)
• ranitidine 50 mg IV OR Famotidine 20 mg IV ^
• dexamethasone 10 mg IV ^

* MUST give diphenhydramine prior to each ramucirumab dose. Also give acetaminophen and/or dexamethasone IV with prior grade 1 or 2 IR to ramucirumab.

^ Consider discontinuing ranitidine and/or dexamethasone if there was no IR in the first 2 paclitaxel doses.

On day 8 (paclitaxel only)**:

To be given 30-60 minutes prior to paclitaxel infusion.

• Dexamethasone 10 mg IV
• Diphenhydramine 25-50 mg IV/PO
• Ranitidine 50 mg IV OR Famotidine 20 mg IV

**Consider discontinuing pre-medications if there was no IR in the first 2 paclitaxel doses.
 

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs. 

Do not treat until the following have been met (see table below). If paclitaxel cannot be given on day 1, delay for up to 28 days and then restart; if it cannot be given on day 8 or 15, the dose should be skipped.  If ramucirumab cannot be given, the dose should be skipped. 

Table 1: Parameters to be Met Before Treatment

Table 2: Dose Levels

_{*Do not restart until hematologic toxicity has recovered to levels described to Table 1, and non-hematologic toxicity < grade 2 or baseline.}

_{**If urine protein does not return to < 2 g/24 hours, discontinue. ***If must be held on day 8 or 15, the dose should be skipped.}

Management of Infusion-related reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Ramucirumab:

Paclitaxel:

^Ramucirumab is only funded if used in combination with paclitaxel based on the results of the RAINBOW study (Wilke et al., 2014).

For paclitaxel, patients with hepatic impairment may be at risk of myelosuppression (see table for suggested dosage adjustment). For ramucirumab, no dosage adjustment is recommended for patients with hepatic impairment. New onset or worsening ascites, encephalopathy or hepatorenal syndrome can occur in patients with Child-Pugh B or C cirrhosis. Treat only if potential benefit outweighs risk in these patients.
 

For paclitaxel, no dosage adjustment required, but consider for patients with HIV-AIDS if creatinine ≥ 2 x ULN. For ramucirumab, no dosage adjustment is recommended in mild to moderate renal impairment. No data is available for CrCl < 30 ml//min.

No dose adjustment required. No overall differences in safety or effectiveness were observed between patients ≥65 years compared with younger patients. Elderly patients on paclitaxel may be more at risk of toxicity.
 

Dosage based on ethnicity

Higher incidences of grade 3 proteinuria and nephrotic syndrome were reported in Asian patients living in East Asia compared to Caucasian patients.

Refer to ramucirumab drug monograph(s) for additional details of adverse effects

Refer to ramucirumab, PACLitaxel drug monograph(s) for additional details

• Caution with the use of paclitaxel and CYP2C8/CYP3A4 substrates, inducers, or inhibitors.
• Use of angiogenesis inhibitors and bisphosphates may increase the risk of osteonecrosis of the jaw.

Refer to ramucirumab, PACLitaxel drug monograph(s) for additional details

Administration - Paclitaxel:

• In order to minimize patients’ exposure to DEHP leaching from PVC bags or sets, use polyolefin or polypropylene infusion bags and polyethylene-lined administration sets (with a 0.22 micron in-line filter).
• Dilute in Normal Saline or 5% Dextrose to a final concentration of 0.3-1.2 mg/mL.
• For weekly dosing, may be infused over 1 hour - mix in 250mL bag as above (not approved by manufacturer).
• Extended infusion of paclitaxel is not recommended as primary prophylaxis to reduce paclitaxel IRs.
• Excessive shaking, agitation, or vibration may induce precipitation and should be avoided.
• Precipitation may rarely occur with infusions longer than 3 hours.

Administration - Ramucirumab:

• Administer as IV infusion only. DO NOT administer as IV push or bolus.
• Withdraw required volume and transfer to an empty IV container.
• Dilute with normal saline to a total volume of 250 mL. DO NOT use dextrose as a diluent.
• Gently invert container to mix. DO NOT shake.
• Give ramucirumab before administering paclitaxel when used in combination.
• Infuse IV over approximately 60 minutes (maximum rate 25 mg/min) using a separate infusion line, with a protein sparing 0.22 micron filter.
• Flush the line with normal saline at the end of the infusion.
• DO NOT dilute or co-administer with other electrolytes or medications.
• Refrigerate unopened vials in original carton (2-8°C).  Protect from light and DO NOT freeze.

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
 

Contraindications:

• Patients with a history of severe hypersensitivity reactions to paclitaxel, other drugs formulated in Cremophor EL (polyethoxylated castor oil), or ramucirumab.
• Patients with severe baseline neutropenia (<1.5 x 10⁹/L; < 1 x 10⁹/L for patients with AIDS-related Kaposi’s) (with paclitaxel)

Warnings/Precautions:

• Paclitaxel contains ethanol, and is administered with agents such as antihistamines which cause drowsiness. Patients should be cautioned regarding driving and the use of machinery.
• Treat with ramucirumab only if potential benefit outweighs risk in patients with Child-Pugh Class B or C cirrhosis as clinical deterioration has been reported.
• Use with caution in patients with known or increased risk of coronary artery disease and/or those receiving cardiotoxic chemotherapy.
• Use with caution in patients at risk of bleeding, including those receiving concomitant antiplatelets and/or anticoagulants.
• Ramucirumab has not been evaluated in patients with serious or non-healing wounds and may impair healing. Withhold prior to surgery until the wound has fully healed.
• Use with caution in patients with risk factors for GI perforation, including intra-abdominal metastases, inflammatory bowel disease, diverticulitis, ischemic bowel, peptic ulcers, obstruction and injury from endoscopy and surgery.

Pregnancy/Lactation:

• Paclitaxel and ramucirumab are not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment and at least for 6 months after the last dose.
• Breastfeeding is not recommended during treatment and for at least 3 months after the last dose.
• Fertility may be affected.

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Paclitaxel and ramucirumab drug monographs, Ontario Health (Cancer Care Ontario).

Wilke H, Muro K, Van Cutsem E, et al; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35.

• Systemic Therapy for Advanced Gastric and Gastro-Esophageal Carcinoma