Mvasi

Mvasi can make it easier for you to bleed. Seek emergency medical attention if you have any bleeding that will not stop. You may also have bleeding on the inside of your body.

Call your doctor if you have: signs of bleeding in your digestive tract--feeling very weak or dizzy, severe stomach pain, black or bloody stools, coughing up blood or vomit that looks like coffee grounds; or signs of bleeding in the brain--sudden numbness or weakness, slurred speech, severe headache, problems with vision or balance.

Do not use this medicine within 28 days before or after a planned surgery.

Call your doctor for instructions if you miss an appointment for your Mvasi injection.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Mvasi can make it easier for you to bleed. Call your doctor or seek emergency medical attention if you have:

• easy bruising, unusual bleeding (nose, mouth, vagina, rectum), or any bleeding that will not stop;

• signs of bleeding in your digestive tract--severe stomach pain, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds; or

• signs of bleeding in the brain--sudden numbness or weakness (especially on one side of the body), sudden severe headache, problems with vision or balance.

Mvasi can cause a rare but serious neurologic disorder affecting the brain. Symptoms may occur within hours of your first dose, or they may not appear for up to a year after your treatment started. Call your doctor at once if you have extreme weakness or tiredness, headache, confusion, vision problems, fainting, or seizure (blackout or convulsions).

Some people receiving Mvasi have developed a fistula (an abnormal passageway) within the throat, lungs, gallbladder, kidney, bladder, or vagina. Call your doctor if you have: chest pain and trouble breathing, stomach pain or swelling, urine leakage, or if you feel like you are choking and gagging when you eat or drink.

Also call your doctor if you have:

• pain, swelling, warmth, or redness in one or both legs;

• chest tightness or heavy feeling, pain spreading to the jaw or shoulder, nausea, sweating, general ill feeling;

• missed menstrual periods;

• low white blood cell counts--fever, swollen gums, painful mouth sores, skin sores, cold or flu symptoms, cough, trouble breathing;

• signs of any skin infection--sudden redness, warmth, swelling, or oozing, or any skin wound or surgical incision that will not heal; or

• increased blood pressure--severe headache, blurred vision, pounding in your neck or ears, anxiety, nosebleed.

Side effects may be more likely in older adults.

Common side effects may include:

• nosebleed, rectal bleeding;

• increased blood pressure;

• headache, back pain;

• dry or watery eyes;

• dry or flaky skin;

• runny nose, sneezing; or

• changes in your sense of taste.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other drugs may affect Mvasi, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

Applies to bevacizumab: intravenous solution

Along with its needed effects, bevacizumab (the active ingredient contained in Mvasi) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking bevacizumab:

• Black, tarry stools
• bleeding gums
• body aches or pain
• burning, tingling, numbness, or pain in the hands, arms, feet, or legs
• chest pain or discomfort
• chills
• cloudy urine
• cough
• cracks in the skin
• decreased urine output
• difficult or labored breathing
• dilated neck veins
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• ear congestion
• extreme tiredness or weakness
• fever
• irregular breathing
• irregular heartbeat
• lack or loss of strength
• lightheadedness
• loss of appetite
• loss of heat from the body
• loss of voice
• mood changes
• nasal congestion
• nervousness
• pain
• pain, redness, or swelling in the arm or leg
• painful or difficult urination
• pinpoint red spots on the skin
• pounding in the ears
• rapid breathing
• redness
• runny nose
• seizures
• sensation of pins and needles
• slow or fast heartbeat
• sore throat
• sores on the skin
• sores, ulcers, or white spots on the lips or in the mouth
• stabbing pain
• sunken eyes
• sweating
• swelling of the face, fingers, feet, or lower legs
• swelling or inflammation of the mouth
• swollen glands
• thirst
• tightness in the chest
• trouble breathing
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds
• watery or bloody diarrhea
• weight gain
• wrinkled skin
• yellow skin

• Bone pain
• difficulty with swallowing
• fainting
• severe constipation
• severe vomiting
• stomach pain or tenderness

• Back pain
• blisters
• blurred vision
• confusion
• dizziness
• drowsiness
• headache
• increased thirst
• loss of consciousness
• muscle pain or cramps
• open sores
• pale skin

• Bloody mucus or unexplained nosebleeds
• hoarseness
• sudden weakness in the arms or legs
• sudden, severe chest pain
• voice changes

Some side effects of bevacizumab may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Belching
• bloody nose
• change in taste or bad unusual or unpleasant (after) taste
• change in walking and balance
• clumsiness or unsteadiness
• diarrhea
• dry mouth
• excess flow of tears
• hair loss
• heartburn
• indigestion
• stomach discomfort or upset
• thinning of the hair
• weight loss

For Healthcare Professionals

Applies to bevacizumab: intravenous solution

Gastrointestinal

Very common (10% or more): Abdominal pain (up to 61%), vomiting (up to 52%), anorexia (up to 43%), constipation (up to 40%), diarrhea (up to 34%), stomatitis (up to 32%), dyspepsia (up to 24%), gastrointestinal hemorrhage (up to 24%), flatulence (up to 19%)
Common (1% to 10%): Dry mouth, colitis, constipation, nausea
Very rare (less than 0.01%): TE fistula, upper aerodigestive tract hemorrhage
Frequency not reported: Intestinal obstruction, intestinal necrosis, mesenteric venous occlusion, ileus, anastomotic ulceration, gastrointestinal perforation and wound dehiscence (complicated by intra-abdominal abscesses), tracheoesophageal fistulae[Ref]

All three TE fistulas occurred during the bevacizumab maintenance phase of the study in the context of persistent esophagitis. Additionally, six other cases of TE fistula have been reported in other lung and esophageal cancer studies using bevacizumab and chemotherapy alone or with concurrent radiation treatment.

The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intraabdominal abscess) in patients with colorectal cancer and in patients with non-small cell lung cancer (NSCLC) receiving bevacizumab was 2.4% and 0.9%, respectively.[Ref]

Cardiovascular

Very common (10% or more): Hypertension (up to 34%), hypotension (up to 15%)
Common (1% to 10%): Deep vein thrombosis, congestive heart failure
Frequency not reported: Arterial thromboembolic events (including cerebrovascular accident (stroke), myocardial infarction, transient ischemic attack, angina), fatal arterial thrombotic events, cerebral ischemia, supraventricular tachycardia, both serious and non-serious hemorrhagic events[Ref]

Risk factors for the development of arterial thromboembolic events have included a history of arterial thromboembolism prior to bevacizumab exposure, age 65 years and above, and bevacizumab therapy. These events have occurred at a higher rate in these high-risk groups.

In one study, the rate of congestive heart failure (defined as NCI-CTC grade 3 and 4) in the bevacizumab plus paclitaxel arm was 2.2% versus 0.3% in the control arm. Among patients receiving anthracyclines, the rate of CHF was 3.8% for bevacizumab treated patients and 0.6% for patients receiving paclitaxel alone. Congestive heart failure occurred in six of 44 (14%) patients with relapsed acute leukemia (a non-FDA approved indication) receiving bevacizumab and concurrent anthracyclines in a single arm study. The safety of continuation or resumption of bevacizumab in patients with cardiac dysfunction has not been studied.[Ref]

Nervous system

Very common (10% or more): Dizziness (up to 26%), sensory neuropathy (24%)
Common (1% to 10%): Confusion, abnormal gait, CNS hemorrhage, cerebrovascular ischemia
Rare (less than 0.1%): Brain-capillary leak syndrome (reversible posterior hyponatremia
hypertensive encephalopathy
Frequency not reported: Dysgeusia[Ref]

RPLS is a neurological disorder associated with hypertension, fluid retention, and cytotoxic effects of immunosuppressive drugs on the vascular endothelium. The syndrome can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present, but is not necessary for diagnosis. The onset of symptoms has been reported to occur from sixteen hours to one year after initiation of bevacizumab. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS.[Ref]

Hematologic

Very common (10% or more): Leukopenia (37%), neutropenia (21%)
Common (1% to 10%): Thrombocytopenia
Frequency not reported: Hemorrhagic events, pancytopenia, febrile neutropenia, decreased hemoglobin, anemia, prothrombin time prolongations, infection with severe neutropenia[Ref]

Hepatic

Postmarketing reports: Gallbladder perforation

Metabolic

Very common (10% or more): Hyperglycemia (up to 26%), hypomagnesemia (up to 24%), hyponatremia (up to 19%), hypoalbuminemia (16%), weight loss (up to 16%), hypokalemia (up to 16%)
Common (1% to 10%): Bilirubinemia
Frequency not reported: Increased blood potassium, decreased blood phosphorus, increased blood alkaline phosphatase[Ref]

Musculoskeletal

Very common (10% or more): Myalgia (up to 15%)
Common (1% to 10%): Bone pain, back pain
Postmarketing reports: Osteonecrosis of the jaw[Ref]

Genitourinary

Frequency not reported: Ureteral stricture[Ref]

Respiratory

Very common (10% or more): Upper respiratory infection (up to 47%), severe or fatal hemoptysis (up to 31%), epistaxis (up to 35%), dyspnea (up to 26%)
Frequency not reported: Pulmonary hypertension, fatal pulmonary hemorrhage, nasal septum perforation
Common (1% to 10%): Voice alteration[Ref]

Patients with recent hemoptysis (greater than or equal to 1/2 tsp of red blood) should not receive bevacizumab.

In study 6, four of 13 (31%) bevacizumab-treated patients with squamous cell histology and two of 53 (4%) bevacizumab-treated patients with histology other than squamous cell, experienced serious or fatal pulmonary hemorrhage as compared to none of the 32 (0%) patients receiving chemotherapy alone. In study 5, the rate of pulmonary hemorrhage requiring medical intervention for the paclitaxel, carboplatin, plus bevacizumab arm was 2.3% (10 of 427) compared to 0.5% (2 of 441) for the paclitaxel plus carboplatin alone arm. There were seven deaths due to pulmonary hemorrhage reported by investigators in the paclitaxel, carboplatin, plus bevacizumab arm as compared to one in the paclitaxel plus carboplatin alone arm. Generally, these serious hemorrhagic events presented as major or massive hemoptysis without a history of minor hemoptysis during bevacizumab therapy.[Ref]

Renal

Kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

In study 5, patients age 65 and older receiving carboplatin, paclitaxel, and bevacizumab (the active ingredient contained in Mvasi) had a greater relative risk for proteinuria as compared to younger patients.[Ref]

Very common (10% or more): Proteinuria (up to 36%)
Uncommon (0.1% to 1%): Nephrotic syndrome[Ref]

Ocular

Very common (10% or more): Lacrimation increased
Postmarketing reports: Cases of serious ocular adverse reactions have been reported following unapproved intravitreal use of this drug compounded from vials approved for IV administration. These reactions included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitreitis, retinal detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular hemorrhage (such as vitreous hemorrhage or retinal hemorrhage and conjunctival hemorrhage). Some of these reactions have resulted in various degrees of visual loss, including permanent blindness.[Ref]

It has been suggested that reduction in macular edema after treatment may have resulted in anatomic changes at the fovea and may have triggered the visual hallucinations.[Ref]

Dermatologic

Very common (10% or more): Alopecia (up to 32%)
Common (1% to 10%): Rash/desquamation, skin ulcer
Frequency not reported: Exfoliative dermatitis, skin discoloration
Postmarketing reports: Necrotizing fasciitis[Ref]

Other

Very common (10% or more): Asthenia (up to 74%), pain (up to 62%), fatigue (up to 80%), headache (up to 37%), peripheral edema (up to 22%), taste disorder (up to 9%)
Common (1% to 10%): Infection with an unknown ANC
Uncommon (0.1% to 1%): Nongastrointestinal fistula formation, infection without neutropenia
Frequency not reported: Mesenteric venous occlusion, syncope, dehydration, somnolence, polyserositis, polyserositis[Ref]

Immunologic

Frequency not reported: Sepsis, wound healing complications, urinary tract infection, positive assays for treatment-emergent anti-bevacizumab[Ref]

Some side effects of Mvasi may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.