How to use AVASTIN

Avastin

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AVASTIN®
(bevacizumab) Solution for Intravenous Infusion

DRUG DESCRIPTION

Avastin (bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Avastin has an approximate molecular weight of 149 kD. Bevacizumab is produced in a mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.

Avastin is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for intravenous infusion. Avastin is supplied in 100 mg and 400 mg preservative-free, single-use vials to deliver 4 mL or 16 mL of Avastin (25 mg/mL). The 100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg product is formulated in 960 mg a,a-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP.

What are the possible side effects of bevacizumab (Avastin)?

Bevacizumab can cause a rare but serious neurologic disorder affecting the brain. Symptoms include headache, confusion, vision problems, feeling very weak or tired, fainting, and seizure (blackout or convulsions). These rare symptoms may occur within hours of your first dose of bevacizumab, or they may not appear for up to a year after your treatment started. Call your doctor at once if you have any of these side effects.

Some people receiving a bevacizumab injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you...

Read All Potential Side Effects and See Pictures of Avastin »

What are the precautions when taking bevacizumab (Avastin)?

Before using bevacizumab, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: stomach/intestinal ulcers, recent bloody vomiting or coughing up blood, recent major surgery, a fistula (an abnormal tunnel connecting two body cavities such as the bladder and the vagina).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: high blood pressure, heart disease or blood clots (arterial vessels), kidney...

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WARNING

GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Gastrointestinal Perforations

The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]

Surgery and Wound Healing Complications

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]

Hemorrhage

Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS.]

What is Avastin?

Avastin is approved for:

• Metastatic colorectal cancer (mCRC) for first- or second-line treatment in combination with intravenous 5-fluorouracil–based chemotherapy. It is also approved to treat mCRC for second-line treatment when used with fluoropyrimidine-based (combined with irinotecan or oxaliplatin) chemotherapy after cancer progresses following a first-line treatment that includes Avastin
  • Avastin is not approved for use after the primary treatment of colon cancer that has not spread to other parts of the body.
• Advanced nonsquamous non–small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease
• Metastatic kidney cancer (mRCC) when used with interferon alfa
• Glioblastoma (GBM) when taken alone in adult patients whose cancer has progressed after prior treatment. The effectiveness of Avastin in GBM is based on tumor response. Currently, no data have shown whether or not Avastin improves disease-related symptoms or survival in people previously treated for GBM

Possible Serious Side Effects

Everyone reacts differently to Avastin therapy. So it’s important to know what the side effects are. Although some people may have a life-threatening side effect, most do not.

Your doctor will stop treatment if any serious side effects occur. Be sure to contact your health care team if you have symptoms related to these side effects.

The most serious side effects (not common, but sometimes fatal):

• Gastrointestinal (GI) perforation. A hole that develops in your stomach or intestine. Symptoms include pain in the abdomen, nausea, vomiting, constipation, or fever
• Wounds that don’t heal. A cut made during surgery can be slow to heal or may not fully heal. Avastin should not be used for at least 28 days before or after surgery and until surgical wounds are fully healed
• Serious bleeding. This includes vomiting or coughing up blood; bleeding in the stomach, brain, or spinal cord; and vaginal bleeding. If you recently coughed up blood or had serious bleeding, do not take Avastin

Other possible serious side effects:

• Abnormal passage in the body. This forms from one part of the body to another and can sometimes be fatal
• Stroke or heart problems. These include blood clots, mini-stroke, heart attack, and chest pain. These can sometimes be fatal
• Severe high blood pressure. Blood pressure that severely spikes or shows signs of affecting the brain. Blood pressure should be monitored every 2 to 3 weeks while on Avastin and after stopping treatment
• Nervous system and vision problems. Symptoms include high blood pressure, headache, seizure, sluggishness, confusion, and blindness
• Kidney problems. These may be caused by too much protein in the urine and can sometimes be fatal
• Infusion reactions. These may include difficulty breathing, chest pain, and excessive sweating. Your doctor or nurse will monitor you for signs of infusion reactions
• Fertility issues for women. Avastin could cause a woman’s ovaries to stop working and may impair her ability to have children

Additional Safety Information

The most common side effects of Avastin are:

Nosebleeds Headache High blood pressure Inflammation of the nose Too much protein in the urine Taste change

Dry skin Rectal bleeding Tear production disorder Back pain Inflammation of the skin

Avastin is not right for everyone. Talk to your doctor if you:

• Are pregnant, may be pregnant, or are breast-feeding. Avastin may harm the fetus or a child that is nursing. If you stop Avastin, you should keep using birth control for at least 6 months after your last dose before trying to become pregnant
• Are undergoing surgery. Don’t take Avastin for at least 28 days before or after surgery and until surgical wounds are fully healed

If you have any questions about your condition or treatment, talk to your doctor.

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at (888) 835-2555.

Cost of Living: Avastin, Zaltrap, Yervoy, Provenge, Erbitux, Gleevec, Tasigna, Sprycel

The Cost of Living: New drugs could extend cancer patients’ lives—by days. At a cost of thousands and thousands of dollars. Prompting some doctors to refuse to use them.

Avastin, $5,000/month; Zaltrap, $11,000/month; Yervoy, $39,000/month; Provenge, $93,000/course of treatment; Erbitux, $8,400/month; Gleevec, $92,000/year; Tasigna, $115,000/year; Sprycel, $123,000/year. (Photo: Illustrations by Remie Geoffroi)

On August 3, 2012, the Food and Drug Administration approved a new cancer drug called Zaltrap as a safe and effective treatment for patients with advanced colon cancer. The approval was based on a large-scale clinical trial that showed that Zaltrap, given in combination with three previously approved drugs to patients who had failed initial therapy, extended median overall survival by 42 days.

No one knew the price of Zaltrap at that point, but Leonard Saltz, who heads the gastrointestinal oncology group at Memorial Sloan-Kettering Cancer Center, had a sense of what was coming. Zaltrap’s effectiveness, in his opinion, was almost identical to that of Avastin, an FDA-approved cancer drug that had also been targeted at that same patient population. Several weeks earlier, Saltz had traveled to Chicago to inflict a little premonitory sticker shock on his medical colleagues. He reviewed the recent clinical results of both Zaltrap and Avastin when used as a “second line” treatment, after initial treatment had failed. As Saltz reminded the other oncologists, Avastin was modestly effective as a second-line treatment—it extended median overall survival by 42 days, the same as Zaltrap—but it cost about $5,000 a month and, like Zaltrap, would have to be taken for many months to achieve that modest clinical benefit. The overall cost was so high that Saltz devoted the end of his talk to a back-of-the-envelope calculation, delivered via PowerPoint, that recast the question in terms of health-care costs: If you extended the 42 days survival to a year, “what is the cost of Avastin for one year of human life saved?”

The answer was astounding, even to doctors who have grown inured to the zero-gravity economics of cancer pharmaceuticals. As Saltz worked his way through slide 73 of 78, he arrived at the bottom line: $303,000.

“Now, that’s essentially the cost of the bare-bones drug,” Saltz later explained to me in his office at Sloan-Kettering. “It’s parts, not labor. No money for doctors; no money for nurses; no money for pharmacists; no money for real estate, heat, and lights; no money for the needles, the IV tubing, the IV fluids, the anti-nausea medicines, the other chemotherapies that are given, because Avastin doesn’t do anything by itself. It has to be given with other drugs … I want to emphasize it’s not that we can have a year of life saved for $303,000. That’s probably less than half of what the actual cost would be when you factor in everything.” Zaltrap, he figured, was probably going to be in the same range.

Saltz’s message was not entirely unexpected. He has been warning about the danger of rising drug prices, to patients and to the health-care system in general, for the last decade. Having made this point to his colleagues, Saltz packed up his computer, took the next flight back to New York, and, after the FDA approved Zaltrap in early August, began to prepare—“not with great enthusiasm,” he conceded—the Zaltrap presentation he would deliver to the hospital committee responsible for approving any new drugs for Sloan-­Kettering’s pharmacy.

Then, on August 31, he received an e-mail from a pharmacist at the hospital about the price that Zaltrap’s manufacturers, Sanofi and Regeneron Pharmaceuticals, had set. The pharmacist said, in effect, “Are you aware that this drug is twice as expensive as Avastin?”

“No,” Saltz replied, “I wasn’t aware.”

The pharmacist e-mailed the numbers, and Saltz stared at the figures on his computer screen. Zaltrap, the drug that was extremely similar to Avastin, cost roughly $11,000 a month. (And because that extra 42 days wouldn’t be possible without taking the drug for, say, seven months before—which was roughly what was happening in clinical trials—the price for that six-week life extension could be as high as $75,000.)

“Wow,” he said to himself, “that’s a deal-changer for me.”

That may not seem like a heretical statement, but the unspoken rule in American health care is that doctors should never consider the cost of a medicine that might be beneficial to patients. When the FDA approves a new cancer drug, it analyzes safety and effectiveness only. Medicare is obliged to reimburse payment for the drug, and private insurers in most states must cover the cost. Any doctor who considers cost—or the value of a costly drug—risks being accused of “rationing” health care.

Saltz felt compelled to consider the cost. He didn’t see any medical advantage to Zaltrap for his patients—or any disadvantage, for that matter—but, as he contemplated its price, he thought, I can’t see why I would use this.

That same day, he sent an e-mail to every physician at the hospital who treated patients with colon cancer. “I said, essentially, ‘You all know the data. You were at the meetings. You know what the situation is. What I just learned is this issue regarding the price. Within this context, I can’t envision a scenario where I would plan to use this drug. Can you?’ ”