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Altuzan (Avastin) 100 Mg/4Ml Solution For Infusion 1 Vial

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FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

1 INDICATIONS AND USAGE

1.1 Metastatic Colorectal Cancer (mCRC)

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

1.3 Glioblastoma

1.4 Metastatic Renal Cell Carcinoma (mRCC)

2 DOSAGE AND ADMINISTRATION

2.1 Administration

2.2 Recommended Doses and Schedules

2.3 Preparation for Administration

2.4 Dose Modifications

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1   Gastrointestinal Perforations

5.2    Surgery and Wound Healing Complications

5.3    Hemorrhage

5.4    Non-Gastrointestinal Fistula Formation

5.5    Arterial Thromboembolic Events

5.6    Hypertension

5.7    Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

5.8    Proteinuria

5.9    Infusion Reactions

5.10    Ovarian Failure

6 ADVERSE REACTIONS

6.1   Clinical Trial Experience

6.2    Immunogenicity

6.3    Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1   Pregnancy

8.3   Nursing Mothers

8.4   Pediatric Use

8.5   Geriatric Use

8.6   Females of Reproductive Potential

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1   Mechanism of Action

12.3   Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1   Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2   Animal Toxicology and/or Pharmacology

13.3   Reproductive and Developmental Toxicology

14 CLINICAL STUDIES

14.1   Metastatic Colorectal Cancer (mCRC)

14.2 Lack of Efficacy in Adjuvant Treatment of Colon Cancer

14.3   Unresectable Non–Squamous Non–Small Cell Lung Cancer (NSCLC)

14.4   Glioblastoma

14.5   Metastatic Renal Cell Carcinoma (mRCC)

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Gastrointestinal Perforations

The incidence of gastrointestinal perforation, some fatal, in Altuzan (Avastin)-treated patients ranges from 0.3 to 2.4%. Discontinue Altuzan (Avastin) in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Altuzan (Avastin)-treated patients. Discontinue Altuzan (Avastin) in patients with wound dehiscence. The appropriate interval between termination of Altuzan (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 Altuzan (Avastin) for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).]

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 Altuzan (Avastin). Do not administer Altuzan (Avastin) to patients with serious hemorrhage or recent hemoptysis. [SeeDosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE

1.1 Metastatic Colorectal Cancer (mCRC)

Altuzan (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.

Altuzan (Avastin), in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Altuzan (Avastin)-containing regimen.

Limitation of Use: Altuzan (Avastin) is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).]

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

Altuzan (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.

1.3 Glioblastoma

Altuzan (Avastin) is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Altuzan (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 Altuzan (Avastin). [See Clinical Studies (14.4).]

1.4 Metastatic Renal Cell Carcinoma (mRCC)

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

2 DOSAGE AND ADMINISTRATION

2.1 Administration

Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV) infusion.

·         Do not initiate Altuzan (Avastin) until at least 28 days following major surgery. Administer Altuzan (Avastin) after the surgical incision has fully healed.

·         First infusion: Administer infusion over 90 minutes.

·         Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated; administer all subsequent infusions over 30 minutes if infusion over 60 minutes is tolerated.

2.2 Recommended Doses and Schedules

Patients should continue treatment until disease progression or unacceptable toxicity.

Metastatic Colorectal Cancer (mCRC)

The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with intravenous 5-FU-based chemotherapy.

·         Administer 5 mg/kg when used in combination with bolus-IFL.

·         Administer 10 mg/kg when used in combination with FOLFOX4.

·         Administer 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when used in combination with a fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy regimen in patients who have progressed on a first-line Altuzan (Avastin)-containing regimen.

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

The recommended dose is 15 mg/kg every 3 weeks in combination with carboplatin and paclitaxel.

Glioblastoma

The recommended dose is 10 mg/kg every 2 weeks.

Metastatic Renal Cell Carcinoma (mRCC)

The recommended dose is 10 mg/kg every 2 weeks in combination with interferon alfa.

2.3 Preparation for Administration

Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of Altuzan (Avastin) and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives.

DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION.

2.4 Dose Modifications

There are no recommended dose reductions.

Discontinue Altuzan (Avastin) for:

·         Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ [See Boxed Warning, Warnings and Precautions (5.1, 5.4).]

·         Wound dehiscence and wound healing complications requiring medical intervention [See Warnings and Precautions (5.2).]

·         Serious hemorrhage (i.e., requiring medical intervention[See Boxed Warning, Warnings and Precautions (5.3).]

·         Severe arterial thromboembolic events [See Warnings and Precautions (5.5).]

·         Hypertensive crisis or hypertensive encephalopathy [See Warnings and Precautions (5.6).]

·         Reversible posterior leukoencephalopathy syndrome (RPLS) [See Warnings and Precautions (5.7).]

·         Nephrotic syndrome [See Warnings and Precautions (5.8).]

Temporarily suspend Altuzan (Avastin) for:

·         At least 4 weeks prior to elective surgery [See Warnings and Precautions (5.2).]

·         Severe hypertension not controlled with medical management [See Warnings and Precautions (5.6).]

·         Moderate to severe proteinuria [See Warnings and Precautions (5.8).]

·         Severe infusion reactions [See Warnings and Precautions (5.9).]

3 DOSAGE FORMS AND STRENGTHS

100 mg per 4 mL single-use vial

400 mg per 16 mL single-use vial

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1   Gastrointestinal Perforations

Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Altuzan (Avastin) treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Altuzan (Avastin).

Discontinue Altuzan (Avastin) in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2    Surgery and Wound Healing Complications

Altuzan (Avastin) impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Altuzan (Avastin) was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Altuzan (Avastin) treatment was 15% and in patients who did not receive Altuzan (Avastin), was 4%. [See Adverse Reactions (6.1).]

Altuzan (Avastin) should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Altuzan (Avastin) in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Altuzan (Avastin) and elective surgery is unknown; however, the half-life of Altuzan (Avastin) is estimated to be 20 days. Suspend Altuzan (Avastin) for at least 28 days prior to elective surgery. Do not administer Altuzan (Avastin) until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

Necrotizing fasciitis including fatal cases, has been reported in patients treated with Altuzan (Avastin); usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Altuzan (Avastin) therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).]

5.3    Hemorrhage

Altuzan (Avastin) can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Altuzan (Avastin) compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Altuzan (Avastin) ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Altuzan (Avastin) and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Altuzan (Avastin) were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Altuzan (Avastin)-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Altuzan (Avastin) to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Altuzan (Avastin) in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4    Non-Gastrointestinal Fistula Formation

Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Altuzan (Avastin)-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Altuzan (Avastin) therapy.

Discontinue Altuzan (Avastin) in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5    Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Altuzan (Avastin) compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Altuzan (Avastin) containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Altuzan (Avastin) in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Altuzan (Avastin) therapy after resolution of an ATE has not been studied. Discontinue Altuzan (Avastin) in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6    Hypertension

The incidence of severe hypertension is increased in patients receiving Altuzan (Avastin) as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Monitor blood pressure every two to three weeks during treatment with Altuzan (Avastin). Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Altuzan (Avastin)-induced or -exacerbated hypertension after discontinuation of Altuzan (Avastin).

Temporarily suspend Altuzan (Avastin) in patients with severe hypertension that is not controlled with medical management. Discontinue Altuzan (Avastin) in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7    Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Altuzan (Avastin). RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.

Discontinue Altuzan (Avastin) in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Altuzan (Avastin) therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8    Proteinuria

The incidence and severity of proteinuria is increased in patients receiving Altuzan (Avastin) as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Altuzan (Avastin) in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Altuzan (Avastin) therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Altuzan (Avastin) administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Altuzan (Avastin) in patients with nephrotic syndrome. [SeeDosage and Administration (2.4).] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57)[See Use in Specific Populations (8.5).]

5.9    Infusion Reactions

Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Altuzan (Avastin) were uncommon ( < 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

5.10    Ovarian Failure

The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Altuzan (Avastin) in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Altuzan (Avastin) is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Altuzan (Avastin). [See Adverse Reactions (6.1), Use in Specific Populations (8.6).]

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the label:

·         Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

·         Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

·         Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

·         Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

·         Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

·         Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

·         Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

·         Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

·         Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

The most common adverse reactions observed in Altuzan (Avastin) patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Altuzan (Avastin) was discontinued in 8.4 to 21% of patients because of adverse reactions.

6.1   Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Altuzan (Avastin) in 4599 patients with CRC, non-squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Altuzan (Avastin). [See Clinical Studies (14).] The population was aged 18-89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first- and second-line mCRC patients who received a median of 10 doses of Altuzan (Avastin), 480 first-line metastatic NSCLC patients who received a median of 8 doses of Altuzan (Avastin), 163 glioblastoma patients who received a median of 9 doses of Altuzan (Avastin), and 337 mRCC patients who received a median of 16 doses of Altuzan (Avastin). These data also reflect exposure to Altuzan (Avastin) in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Altuzan (Avastin), 669 female adjuvant CRC patients who received a median of 23 doses of Altuzan (Avastin) and exposure to Altuzan (Avastin) in 403 previously untreated patients with diffuse large B-cell lymphoma (DLBCL) who received a median of 8 doses of Altuzan (Avastin). Altuzan (Avastin) is not approved for use in MBC, adjuvant CRC, or DLBCL.

Surgery and Wound Healing Complications

The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Altuzan (Avastin) as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Altuzan (Avastin) as compared to 4% (1/25) of patients who received bolus-IFL alone.

In Study 6, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Altuzan (Avastin) alone arm and 1/79 patients in the Altuzan (Avastin) plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage

The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Altuzan (Avastin) compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Altuzan (Avastin) when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events

The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Altuzan (Avastin) and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, more patients in the Altuzan (Avastin) containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra-abdominal venous thrombosis (10 vs. 5 patients).

The risk of developing a second thromboembolic event while on Altuzan (Avastin) and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus-IFL plus Altuzan (Avastin) arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Altuzan (Avastin) and 3% (1/30) of patients receiving bolus-IFL alone.

In a second, randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Altuzan (Avastin) containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Altuzan (Avastin) plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Altuzan (Avastin) treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Altuzan (Avastin) treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Neutropenia and Infection

The incidences of neutropenia and febrile neutropenia are increased in patients receiving Altuzan (Avastin) plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Altuzan (Avastin) (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Altuzan (Avastin) (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Altuzan (Avastin) vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Altuzan (Avastin) arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Altuzan (Avastin) arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Altuzan (Avastin) alone. The incidence of any grade of infection in patients receiving Altuzan (Avastin) alone was 55% and the incidence of Grade 3–5 infection was 10%.

Proteinuria

Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Altuzan (Avastin). Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Altuzan (Avastin) in 30% of the patients who developed proteinuria (Study 8).

In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Altuzan (Avastin) in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Altuzan (Avastin) was re-initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re-initiated Altuzan (Avastin), 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.8).]

Congestive Heart Failure (CHF)

The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Altuzan (Avastin) compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Altuzan (Avastin) is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Altuzan (Avastin) plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Altuzan (Avastin) as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Altuzan (Avastin) in patients with cardiac dysfunction has not been studied.

In previously untreated patients with diffuse large B-cell lymphoma (DLBCL), an indication for which Altuzan (Avastin) is not approved, the incidence of CHF and decline in left-ventricular ejection fraction (LVEF) were signficantly increased in the Altuzan (Avastin) plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R-CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R-CHOP therapy, the incidence of CHF was 10.9% in the Altuzan (Avastin) plus R-CHOP arm compared to 5.0% in the R-CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Altuzan (Avastin) plus R-CHOP arm (10.4%) compared to the R-CHOP alone arm (5.0%). Time to onset of left-ventricular dysfunction or CHF was 1-6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Altuzan (Avastin) arm compared to 82% in the control arm.

Ovarian Failure

The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n

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Altuzan (Avastin) 100 Mg/4Ml Solution For Infusion 1 Vial

  • Brand: Roche
  • Product Code: 8699505762821
  • Availability: In Stock
  • $898.00

Tags: Altuzan (Avastin) 100 Mg/4Ml Solution For Infusion 1 Vial, Roche, All Products, Anticancer