Provayblue

In the U.S.

• Provayblue

Available Dosage Forms:

• Solution

Therapeutic Class: Diagnostic Agent, Kidney Function

A nurse or other trained health professional will give you this medicine in a hospital. This medicine is given through a needle placed in one of your veins. The medicine must be injected slowly, so your IV tube will need to stay in place for 5 to 30 minutes.

Along with its needed effects, a medicine 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:

• Agitation
• bluish-colored lips, fingernails, or palms
• confusion
• cough
• dark urine
• diarrhea
• difficulty breathing
• difficulty swallowing
• dizziness or lightheadedness
• fast heartbeat
• fever
• headache
• hives or welts, itching, or skin rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• overactive reflexes
• pale skin
• poor coordination
• rapid heart rate
• redness of the skin
• restlessness
• shivering
• sore throat
• sweating
• talking or acting with excitement you cannot control
• tightness in the chest
• trembling or shaking
• twitching
• unusual bleeding or bruising
• unusual tiredness or weakness

Get emergency help immediately if any of the following symptoms of overdose occur:

• Abdominal or stomach pain
• bigger, dilated, or enlarged pupils (black part of the eye)
• blue staining of the urine, skin, and mucous membranes
• bluish-colored lips, fingernails, or palms
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• confusion
• dark urine
• difficulty breathing
• dizziness or lightheadedness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fear
• fever
• headache
• increased sensitivity of the eyes to light
• nausea
• pale skin
• rapid heart rate
• rapid shallow breathing
• shakiness in the legs, arms, hands, or feet
• sore throat
• tightness in the chest
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting

Some side effects 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:

• Change in taste
• changes in skin color
• feeling hot or cold
• increased sweating
• loss of taste
• muscle or joint pain
• pain at the infusion site
• pain in the arms or legs

• Back pain
• bruising
• chills
• general feeling of discomfort or illness
• large, flat, blue or purplish patches in the skin
• loss of appetite
• muscle aches and pains
• muscle spasm
• runny nose
• trouble sleeping

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• If you have an allergy to methylene blue or any other part of ProvayBlue.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have G6PD deficiency.
• If you are pregnant or may be pregnant. Do not take this medicine if you are pregnant.
• If you are breast-feeding. Do not breast-feed while you take ProvayBlue or within 8 days after your last dose.
• If this medicine is not being given into a vein. This medicine must not be given into the spine. Talk with the doctor.

This is not a list of all drugs or health problems that interact with ProvayBlue.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a vein.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

Injection: 50 mg/10 mL (5 mg/mL) clear dark blue solution in single-dose ampules

ProvayBlue™ is contraindicated in the following conditions:

• Severe hypersensitivity reactions to methylene blue or any other thiazine dye [see Warnings and Precautions ( 5.2)] .
• Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia [see Warnings and Precautions ( 5.3, 5.4)]

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

The development of serotonin syndrome has been reported with use of methylene blue class products. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors). Some of the reported cases were fatal. Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Avoid concomitant use of ProvayBlue™ with serotonergic drugs.

Patients treated with ProvayBlue™ should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of ProvayBlue™, and initiate supportive treatment. Inform patients of the increased risk of serotonin syndrome and advise them to not to take serotonergic drugs within 72 hours after the last dose of ProvayBlue™ [see Drug Interactions ( 7), Patient Counseling Information ( 17)] .

Hypersensitivity

Anaphylactic reactions to methylene blue class products have been reported. Patients treated with ProvayBlue™ should be monitored for anaphylaxis. If anaphylaxis or other severe hypersensitivity reactions (e.g., angioedema, urticaria, bronchospasm) should occur, discontinue use of ProvayBlue™ and initiate supportive treatment. ProvayBlue™ is contraindicated in patients who have experienced anaphylaxis or other severe hypersensitivity reactions to a methylene blue class product in the past.

Lack of Effectiveness

Methemoglobinemia may not resolve or may rebound after response to treatment with ProvayBlue™ in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with ProvayBlue™ through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of ProvayBlue™ or if methemoglobinemia rebounds after a response, consider additional treatment options [see Dosage and Administration ( 2.2)] .

Patients with glucose-6-phosphate dehydrogenase deficiency may not reduce ProvayBlue™ to its active form in vivo. ProvayBlue™ may not be effective in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Hemolytic Anemia

Hemolysis can occur during treatment of methemoglobinemia with ProvayBlue™. Laboratory testing may show Heinz bodies, elevated indirect bilirubin and low haptoglobin, but the Coombs test is negative. The onset of anemia may be delayed 1 or more days after treatment with ProvayBlue™. The anemia may require red blood cell transfusions. [see Adverse Reactions ( 6.1)]. Use the lowest effective number of doses of ProvayBlue™ to treat methemoglobinemia. Discontinue ProvayBlue™ and consider alternative treatments of methemoglobinemia if severe hemolysis occurs.

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with ProvayBlue™ may result in severe hemolysis and severe anemia. ProvayBlue™ is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency [see Contraindications ( 4)].

Interference with In Vivo Monitoring Devices

• Inaccurate Pulse Oximeter Readings

The presence of methylene blue in the blood may result in an underestimation of the oxygen saturation reading by pulse oximetry. If a measure of oxygen saturation is required during or shortly after infusion of ProvayBlue™, it is advisable to obtain an arterial blood sample for testing by an alternative method.

• Bispectral index monitor

A fall in the Bispectral Index (BIS) has been reported following administration of methylene blue class products. If ProvayBlue™ is administered during surgery, alternative methods for assessing the depth of anesthesia should be employed.

Effects on Ability to Drive and Operate Machinery

Treatment with ProvayBlue™ may cause confusion, dizziness and disturbances in vision [see Adverse Reactions ( 6)] . Advise patients to refrain from driving or engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery until such adverse reactions to ProvayBlue™ have resolved.

Interference with Laboratory Tests

ProvayBlue™ is a blue dye which passes freely into the urine and may interfere with the interpretation of any urine test which relies on a blue indicator, such as the dipstick test for leucocyte esterase.

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

• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs [see Warnings and Precautions ( 5.1)]
• Anaphylaxis [see Warnings and Precautions ( 5.2)]
• Lack of Effectiveness [see Warnings and Precautions ( 5.3)]
• Hemolytic Anemia [see Warnings and Precautions ( 5.4)]
• Interference with In-Vivo Monitoring Devices [see Warnings and Precautions ( 5.5)]
• Effects on Ability to Drive and Operate Machinery [see Warnings and Precautions ( 5.6)]
• Interference with Laboratory Tests [see Warnings and Precautions ( 5.7)]

Clinical Trials 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 safety of ProvayBlue™ was determined in 82 healthy adults of median age of 36 years (range, 19-55 years); 54% were male, and 68% were white. Each individual in the safety population received a single dose of ProvayBlue™ 2 mg/kg intravenously. There was one serious adverse reaction reported (syncope due to sinus pauses of 3-14 seconds). The most common (≥2%) moderate or severe adverse reactions were pain in the extremity (56%), headache (7%), feeling hot (6%), syncope (4%), back pain (2%), hyperhidrosis (2%) and nausea (2%). Table 1 lists the adverse reactions of any severity that occurred in at least 2% of individuals who received ProvayBlue™.

Other adverse reactions reported to occur following administration of methylene blue class products include the following:

Blood and lymphatic system disorders: hemolytic anemia, hemolysis, hyperbilirubinemia, methemoglobinemia

Cardiac disorders: palpitations, tachycardia

Eye disorders: eye pruritus, ocular hyperemia, vision blurred

Gastrointestinal disorders: abdominal pain lower, dry mouth, flatulence, glossodynia, tongue eruption

General disorders and administration site conditions: death, infusion site extravasation, infusion site induration, infusion site pruritus, infusion site swelling, infusion site urticaria, peripheral swelling, thirst

Investigations: elevated liver enzymes

Musculoskeletal and connective tissue disorders: myalgia

Renal and urinary disorders: dysuria

Respiratory, thoracic and mediastinal disorders: nasal congestion, oropharyngeal pain, rhinorrhea, sneezing

Skin and subcutaneous tissue disorders: necrotic ulcer, papule, phototoxicity

Vascular disorders: hypertension

Treatment of Acquired Methemoglobinemia

The efficacy of ProvayBlue™ was assessed on the basis of a methemoglobin decrease of at least 50% within 1 hour after intravenous administration of 1 – 2 mg/kg ProvayBlue™ (or a bioequivalent formulation) in 6 patients identified by retrospective chart review or literature search. The 6 patients included 3 males and 3 females of median age 54 years (range, 6 days to 69 years). The median methemoglobin level at baseline was 37% (range, 11% to 47%). All 6 (100%) patients had a decrease in methemoglobin by at least 50% within 1 hour after treatment.

An additional 41cases of treatment of methemoglobinemia with a methylene blue class product were identified in the published literature. These cases included 24 males and 17 females of median age 33 years (range, 9 days to 80 years). The median methemoglobin level at baseline was 40% (range, 10% to 98%). Of these 41 patients, 37 (90%) had a methemoglobin decrease of at least 50% within 1 hour after intravenous administration of the methylene blue class product.

In a combined analysis of all 47 patients treated intravenously with ProvayBlue™ (or a bioequivalent formulation) or with another methylene blue class product, there was no difference in response rate by dose. The methemoglobin decreased by at least 50% within 1 hour of infusion for 15/17 (88%) of patients treated with 1 mg/kg, 12/13 (92%) treated with 2 mg/kg and 16/17 (94%) treated with a different dose or for those whose dose was not reported.