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ACTEMRA (tocilizumab) Important Safety Information

This information does not take the place of talking to your healthcare provider about either your medical condition or your treatment with ACTEMRA. Talk with your healthcare provider if you have any questions about your treatment with ACTEMRA.

Indication

ACTEMRA is a prescription medicine called an interleukin-6 (IL-6) receptor inhibitor. ACTEMRA is used to treat adults with moderately to severely active rheumatoid arthritis (RA) after at least one other medicine called a tumor necrosis factor (TNF) antagonist has been used and did not work well.

Important Safety Information

Some people have serious infections while taking ACTEMRA, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections.

Other serious side effects of ACTEMRA include tears (perforation) of the stomach and intestines, changes in blood test results, hepatitis B infection in those already carrying the virus, nervous system problems, and serious allergic reactions.

Common side effects with ACTEMRA include upper respiratory tract infections (common cold, sinus infections), headache, and increased blood pressure (hypertension).

Tell your healthcare provider if you plan to become pregnant or are pregnant. It is not known if ACTEMRA will harm your unborn baby. Genentech has a registry for pregnant women who take ACTEMRA. If you are pregnant or become pregnant while taking ACTEMRA, contact the registry at 1-877-311-8972 and talk to your healthcare provider.

Call your healthcare provider for medical advice about any side effects. You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-800-835-2555.

Please see full Prescribing Information and Medication Guide for additional important safety information.

Avastin (bevacizumab) Indications

Metastatic Colorectal Cancer (mCRC)

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Non-Squamous Non–Small Cell Lung Cancer (NSCLC)

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Metastatic Breast Cancer (MBC)

Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Glioblastoma

Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Metastatic Renal Cell Carcinoma (mRCC)

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin Boxed WARNINGS and Additional Important Safety Information

• Gastrointestinal (GI) perforation: Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation
• Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. 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 Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention
• Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)
• Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
• The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions
• The most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
• The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)
• Grade 3-5 (nonhematologic) and grade 4-5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
• Grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E2100 increased by 20.5% in the Avastin plus paclitaxel vs paclitaxel groups. Grade 1–2 adverse events were not collected in Study E2100, and common adverse events of Avastin in combination with paclitaxel for metastatic breast cancer are not known. The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E2100, which occurred at a higher absolute incidence (≥5%) in the Avastin plus paclitaxel vs paclitaxel groups, were sensory neuropathy (24.2% vs 17.5%), hypertension (16.0% vs 1.4%), and fatigue (10.7% vs 5.2%). The rate of CHF (defined as NCI-CTC grade 3–4) in the Avastin plus paclitaxel arm was 2.2% vs 0.3% in the control arm. Among patients receiving anthracyclines, the rate of CHF was 3.8% for Avastin-treated patients and 0.6% for patients receiving paclitaxel alone. Fatal adverse reactions occurred in 1.7% (6/363) of patients who received Avastin plus paclitaxel in Study E2100. Causes of death were GI perforation (2), myocardial infarction (2), and diarrhea/abdominal pain/weakness/hypotension (2)
• In Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection
• In patients receiving Avastin alone or Avastin plus irinotecan, the incidences of Avastin-related adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage
• The most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)

Please see full Prescribing Information for Avastin, including Boxed WARNINGS and additional Important Safety Information.

Herceptin (trastuzumab) Indications

Adjuvant indications: Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature)* breast cancer:

• As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• With docetaxel and carboplatin
• As a single agent following multi-modality anthracycline-based therapy

*ER/PR-negative, tumor size >2 cm, age <35 years, or histological and/or nuclear grade 2 or 3.

Metastatic indications: Herceptin is indicated:

• In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer
• As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

Herceptin Boxed WARNINGS and Additional Important Safety Information

Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure and decreased left ventricular ejection fraction. Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. Exacerbation of chemotherapy-induced neutropenia has also occurred. Herceptin can cause oligohydramnios and fetal harm when administered to a pregnant woman. The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

Please see the Herceptin full prescribing information including Boxed WARNINGS and additional important safety information.

Rituxan (Rituximab) INDICATIONS AND USAGE

Non-Hodgkin's Lymphoma (NHL)

Rituxan® is indicated for the treatment of patients with:

• Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
• Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy
• Non-progressing (including stable disease), low-grade, CD20-positive B-cell NHL, as a single agent, after first-line CVP chemotherapy
• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

Rheumatoid Arthritis

Rituxan is a prescription medication used to treat Rheumatoid Arthritis (RA) with another prescription medicine called methotrexate, to reduce the signs and symptoms of moderate to severe active RA in adults, after treatment with at least one other medicine called a Tumor Necrosis Factor (TNF) antagonist has been used and did not work well enough.

People with serious infections should not receive Rituxan.

Rituxan Boxed WARNINGS and Additional Important Safety Information

The most important serious adverse reactions of Rituxan are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most common adverse reactions of Rituxan observed in patients with RA are hypertension, nausea, upper respiratory tract infection, arthralgia, pruritus, and pyrexia.

Attention healthcare provider: Provide Medication Guide to patient prior to Rituxan infusion.

For additional safety information, please see the full prescribing information, including Boxed WARNINGS and Medication Guide.

XOLAIR (Omalizumab) for Subcutaneous Use Indication

XOLAIR is indicated for adults and adolescents (12 years of age and older) with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with ICS. XOLAIR has been shown to decrease the incidence of asthma exacerbations in these patients. Safety and efficacy have not been established in other allergic conditions.

XOLAIR Safety Information

• XOLAIR should only be administered in a health care setting by health care providers prepared to manage anaphylaxis that can be life- threatening.
• XOLAIR should not be administered to patients who have experienced a severe hypersensitivity reaction to XOLAIR (see Boxed WARNING). XOLAIR should be discontinued in patients who experience a severe hypersensitivity reaction.
• Malignant neoplasms were observed in 20 of 4127 (0.5%) XOLAIR- treated patients compared with 5 of 2236 (0.2%) control patients in clinical studies of asthma and other allergic disorders.
• Patients should be given and instructed to read the Medication Guide before starting treatment and before each subsequent treatment.
• Patients receiving XOLAIR should be told not to decrease the dose of, or stop taking any other asthma medications unless otherwise instructed by their physician.
• The adverse reactions most commonly observed among patients treated with XOLAIR in clinical studies included injection site reaction (45%), viral infections (23%), upper respiratory tract infection (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). These events were observed at similar rates in XOLAIR-treated patients and control patients.

Please see full Prescribing Information, including Boxed WARNING and Medication Guide, for additional Important Safety Information.