Sulfa-Bleu

Methylene Blue:

• Warning: serotonin syndrome with concomitant use of serotonergic drugs
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Sulfa-Bleu (Methylene Blue) reviews

WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS

Sulfa-Bleu (Methylene Blue) may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Avoid concomitant use of Sulfa-Bleu (Methylene Blue) with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors ( 5.1, 7.1).

1 INDICATIONS AND USAGE

Sulfa-Bleu (Methylene Blue) is indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Sulfa-Bleu (Methylene Blue) (methylene blue) is an oxidation-reduction agent indicated for the treatment of pediatric and adult patients with acquired methemoglobinemia. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials. ( 1, 14)

2 DOSAGE AND ADMINISTRATION

• Administer 1 mg/kg intravenously over 5-30 minutes.
• If methemoglobin level remains above 30% or if clinical symptoms persist, give a repeat dose of up to 1 mg/kg one hour after the first dose. ( 2.1)

2.1 Dosage and Administration

• Ensure patent venous access prior to administration of Sulfa-Bleu (Methylene Blue). Do not administer Sulfa-Bleu (Methylene Blue) subcutaneously.
• Monitor vital signs, electrocardiogram and methemoglobin levels during treatment with Sulfa-Bleu (Methylene Blue) and through resolution of methemoglobinemia.
• Administer Sulfa-Bleu (Methylene Blue) 1 mg/kg intravenously over 5-30 minutes.
• If the methemoglobin level remains greater than 30% or if clinical signs and symptoms persist, a repeat dose of Sulfa-Bleu (Methylene Blue) 1 mg/kg may be given one hour after the first dose.
• If methemoglobinemia does not resolve after 2 doses of Sulfa-Bleu (Methylene Blue), consider initiating alternative interventions for treatment of methemoglobinemia.

2.2 Preparation and Storage

Each mL of Sulfa-Bleu (Methylene Blue) contains 5 mg Sulfa-Bleu (Methylene Blue)

Each 10 mL ampule of Sulfa-Bleu (Methylene Blue) contains 50 mg Sulfa-Bleu (Methylene Blue).

Sulfa-Bleu (Methylene Blue) is hypotonic and may be diluted before use in a solution of 50 mL 5% Dextrose in Water (D5W) in order to avoid local pain, particularly in the pediatric population. Use the diluted solution immediately after preparation.

Do not mix with sodium chloride 9 mg/mL (0.9%) solution for injection, because it has been demonstrated that chloride reduces the solubility of Sulfa-Bleu (Methylene Blue).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Keep the ampule in the original package to protect from light.

3 DOSAGE FORMS AND STRENGTHS

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

50 mg/10 mL (5 mg/mL) single-dose ampule. ( 3)

4 CONTRAINDICATIONS

Sulfa-Bleu (Methylene Blue) is contraindicated in the following conditions:

• Severe hypersensitivity reactions to Sulfa-Bleu (Methylene Blue) or any other thiazine dye .
• Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia

Sulfa-Bleu (Methylene Blue) is contraindicated in the following conditions ( 4):

• Severe hypersensitivity to Sulfa-Bleu (Methylene Blue)
• Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity: If severe or life threatening allergic reaction occurs, discontinue Sulfa-Bleu, treat the allergic reaction, and monitor until signs and symptoms resolve ( 5.2)
• Lack of Effectiveness: Consider alternative treatments if there is no resolution of methemoglobinemia after 2 doses ( 2.1, 5.3)
• Hemolytic Anemia: Discontinue Sulfa-Bleu (Methylene Blue) and transfuse ( 5.4)
• Interference with In-Vivo Monitoring Devices: Use methods other than pulse oximetry to assess oxygen satruation ( 5.5)
• Effects on Ability to Drive and Operate Machinery: Advise patients to refrain from these activities until neurologic and visual symptoms have resolved ( 5.6)

5.1 Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

The development of serotonin syndrome has been reported with use of Sulfa-Bleu (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 Sulfa-Bleu (Methylene Blue) with serotonergic drugs.

Patients treated with Sulfa-Bleu (Methylene Blue) should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of Sulfa-Bleu (Methylene Blue), 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 Sulfa-Bleu (Methylene Blue) .

5.2 Hypersensitivity

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

5.3 Lack of Effectiveness

Methemoglobinemia may not resolve or may rebound after response to treatment with Sulfa-Bleu (Methylene Blue) in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with Sulfa-Bleu (Methylene Blue) through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of Sulfa-Bleu (Methylene Blue) or if methemoglobinemia rebounds after a response, consider additional treatment options .

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

5.4 Hemolytic Anemia

Hemolysis can occur during treatment of methemoglobinemia with Sulfa-Bleu. 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 Sulfa-Bleu (Methylene Blue). The anemia may require red blood cell transfusions. . Use the lowest effective number of doses of Sulfa-Bleu (Methylene Blue) to treat methemoglobinemia. Discontinue Sulfa-Bleu (Methylene Blue) and consider alternative treatments of methemoglobinemia if severe hemolysis occurs.

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with Sulfa-Bleu (Methylene Blue) may result in severe hemolysis and severe anemia. Sulfa-Bleu (Methylene Blue) is contraindicated for use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency .

5.5 Interference with In Vivo Monitoring Devices

• Inaccurate Pulse Oximeter Readings

The presence of Sulfa-Bleu (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 Sulfa-Bleu (Methylene Blue), 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 Sulfa-Bleu (Methylene Blue) class products. If Sulfa-Bleu (Methylene Blue) is administered during surgery, alternative methods for assessing the depth of anesthesia should be employed.

5.6 Effects on Ability to Drive and Operate Machinery

Treatment with Sulfa-Bleu may cause confusion, dizziness and disturbances in vision . 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 Sulfa-Bleu (Methylene Blue) have resolved.

5.7 Interference with Laboratory Tests

Sulfa-Bleu (Methylene Blue) 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.

6 ADVERSE REACTIONS

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

• Serotonin Syndrome with Concomitant Use of Serotonergic Drugs
• Anaphylaxis
• Lack of Effectiveness
• Hemolytic Anemia
• Interference with In-Vivo Monitoring Devices
• Effects on Ability to Drive and Operate Machinery
• Interference with Laboratory Tests

The most commonly reported adverse reactions (≥10%) are pain in extremity, chromaturia, dysgeusia, feeling hot, dizziness, hyperhidrosis, nausea, skin, discoloration and headache. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 Sulfa-Bleu (Methylene Blue) 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 Sulfa-Bleu (Methylene Blue) 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 Sulfa-Bleu (Methylene Blue).

Other adverse reactions reported to occur following administration of Sulfa-Bleu (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

7 DRUG INTERACTIONS

7.1 Serotonergic Drugs

Avoid concomitant use of Sulfa-Bleu with medicinal products that enhance serotonergic transmission including SSRIs (selective serotonin reuptake inhibitors), MAO inhibitors, bupropion, buspirone, clomipramine, mirtazapine and venlafaxine; because of the potential for serious CNS reactions, including potentially fatal serotonin syndrome. Although the mechanism is not clearly, understood, literature reports suggest inhibition of MAO by Sulfa-Bleu (Methylene Blue) may be involved. In addition, in vitro studies cannot rule out the potential involvement of CYP 2D6 inhibition by Sulfa-Bleu (Methylene Blue). If the intravenous use of Sulfa-Bleu (Methylene Blue) cannot be avoided in patients treated with serotonergic medicinal products, choose the lowest possible dose and observe closely the patient for CNS effects for up to 4 hours after administration .

7.2 Agents Metabolized by Cytochrome P450 Enzymes

Sulfa-Bleu (Methylene Blue) inhibits a range of CYP isozymes in vitro, including 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5. This interaction could be more pronounced with narrow therapeutic index drugs that are metabolized by one of these enzymes (e.g, digoxin, warfarin, phenytoin, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus). However, the clinical relevance of these in vitro interactions is unknown.

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Only use during pregnancy if the potential benefit justifies the potential risk to the fetus.
• Lactation: Discontinue breast-feeding for up to 8 days after treatment. ( 8.2).
• Renal Insufficiency: Monitor patients longer for toxicity and drug interactions due to delayed clearance. ( 8.6)
• Hepatic Impairment: Monitor patients longer for toxicity and drug interactions due to delayed clearance. ( 8.7)

8.1 Pregnancy

Risk Summary

Sulfa-Bleu (Methylene Blue) may cause fetal harm when administered to a pregnant woman. Intra-amniotic injection of pregnant women with a Sulfa-Bleu (Methylene Blue) class product during the second trimester was associated with neonatal intestinal atresia and fetal death. Sulfa-Bleu (Methylene Blue) produced adverse developmental outcomes in rats and rabbits when administered orally during organogenesis at doses at least 32 and 16 times, respectively, the clinical dose of 1 mg/kg . Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/neonatal adverse reactions

Intra-amniotic injection of a Sulfa-Bleu (Methylene Blue) class product hours to days prior to birth can result hyperbilirubinemia, hemolytic anemia, skin staining, methemoglobinemia, respiratory distress and photosensitivity in the newborn. Following administration of Sulfa-Bleu (Methylene Blue) to a pregnant woman at term, observe the newborn for these adverse reactions and institute supportive care.

Data

Animal Data

Sulfa-Bleu (Methylene Blue) was administered orally to pregnant rats at doses of 50 to 350 mg/kg/day, during the period of organogenesis. Maternal and embryofetal toxicities were observed at all doses of Sulfa-Bleu (Methylene Blue), and were most evident at the 200 and 350 mg/kg/day doses. Maternal toxicity consisted of increased spleen weight. Embryo-fetal toxicities included reduced fetal weight, post-implantation loss, edema, and malformations including enlarged lateral ventricles. The dose of 200 mg/kg (1200 mg/m ²) in rats is approximately 32 times a clinical dose of 1 mg/kg based on body surface area.

Sulfa-Bleu (Methylene Blue) was administered orally to pregnant rabbits at doses of 50, 100, or 150 mg/kg/day, during the period of organogenesis. Maternal death was observed at the Sulfa-Bleu (Methylene Blue) dose of 100 mg/kg. Embryofetal toxicities included spontaneous abortion at all dose levels and a malformation (umbilical hernia) at the 100 and 150 mg/kg/day doses. The dose of 50 mg/kg (600 mg/m ²) in rabbits is approximately 16 times a clinical dose of 1 mg/kg based on body surface area.

8.2 Lactation

Risk Summary

There is no information regarding the presence of Sulfa-Bleu in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including genotoxicity discontinue breast-feeding during and for up to 8 days after treatment with Sulfa-Bleu (Methylene Blue) .

8.4 Pediatric Use

The safety and effectiveness of Sulfa-Bleu (Methylene Blue) have been established in pediatric patients. Use of Sulfa-Bleu (Methylene Blue) is supported by two retrospective case series that included 2 pediatric patients treated with Sulfa-Bleu (Methylene Blue) and 12 treated with another Sulfa-Bleu (Methylene Blue) class product. The case series included pediatric patients in the following age groups: 3 neonates (less than 1 month), 4 infants (1 month up to less than 2 years), 4 children (2 years up to less than 12 years), and 3 adolescents (12 years to less than 17 years). The efficacy outcomes were consistent across pediatric and adult patients in both case series .

8.5 Geriatric Use

The retrospective case series included 3 patients age 65 years and over treated with Sulfa-Bleu (or a bioequivalent formulation) and 5 treated with another Sulfa-Bleu (Methylene Blue) class product. The efficacy outcomes were consistent across adult and elderly patients in both case series . This drug is known to be substantially excreted by the kidney, so the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, treatment of methemoglobinemia in these patients should use the lowest number of doses needed to achieve a response .

8.6 Renal Impairment

Approximately 40% of Sulfa-Bleu (Methylene Blue) is excreted by the kidneys. Patients with any renal impairment should be monitored for toxicities and potential drug interactions for an extended period of time following treatment with Sulfa-Bleu (Methylene Blue).

8.7 Hepatic Impairment

Sulfa-Bleu (Methylene Blue) is extensively metabolized in the liver. Monitor patients with any hepatic impairment for toxicities and potential drug interactions for an extended period of time following treatment with Sulfa-Bleu (Methylene Blue).

10 OVERDOSAGE

Hypotension, wheezing and reduced oxygenation have been reported in patients who received Sulfa-Bleu (Methylene Blue) class products in single doses of 3 mg/kg or more.

Administration of large intravenous doses (cumulative dose ≥ 7 mg/kg ) of a Sulfa-Bleu (Methylene Blue) class product caused nausea, vomiting, precordial pain, dyspnea, tachypnea, chest tightness, tachycardia, apprehension, tremor, mydriasis, blue staining of the urine, the skin and mucous membranes, abdominal pain, dizziness, paresthesia, headache, confusion, mild methemoglobinemia (up to 7%) and electrocardiogram changes (T-wave flattening or inversion) These effects lasted 2-12 hours following administration.

A severe overdosage (single dose of 20 mg/kg or more) of a Sulfa-Bleu (Methylene Blue) class product caused severe intravascular hemolysis, hyperbilirubinemia and death.

In case of overdose of Sulfa-Bleu (Methylene Blue), maintain the patient under observation until signs and symptoms have resolved, monitor for cardiopulmonary, hematologic and neurologic toxicities, and institute supportive measures as necessary.

11 DESCRIPTION

Sulfa-Bleu (Methylene Blue) is an oxidation-reduction agent. Sulfa-Bleu (Methylene Blue) (methylene blue) is a sterile solution intended for intravenous administration. Each Sulfa-Bleu (Methylene Blue), 10 mL ampule contains 50 mg Proveblue ^® Sulfa-Bleu (Methylene Blue) and water for injection q.s. Each mL of solution contains 5 mg Sulfa-Bleu (Methylene Blue) and water for injection q.s.

Sulfa-Bleu (Methylene Blue) is 3,7-bis(dimethylamino)phenothiazin-5-ium, chloride. The molecular formula of Sulfa-Bleu (Methylene Blue) is C ₁₆H ₁₈ClN ₃S and its molecular weight is 319.86 g/mol. Its structural formula is:

Sulfa-Bleu (Methylene Blue) is a clear dark blue solution with a pH value between 3.0 and 4.5. The osmolality is between 10 and 15 mOsm/kg.

Figure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sulfa-Bleu is a water soluble thiazine dye that promotes a non-enyzmatic redox conversion of metHb to hemoglobin. In situ, Sulfa-Bleu (Methylene Blue) is first converted to leucomethylene blue (LMB) via NADPH reductase. It is the LMB molecule which then reduces the ferric iron of metHb to the ferrous state of normal hemoglobin.

12.2 Pharmacodynamics

Low concentrations of Sulfa-Bleu (Methylene Blue) speeds up the in vivo conversion of methemoglobin to hemoglobin. Sulfa-Bleu (Methylene Blue) has been observed to stain tissues selectively. The exposure-response or –safety relationship for methylene is unknown.

Cardiac Electrophysiology

The results of a thorough QT study demonstrated Sulfa-Bleu (Methylene Blue) at an intravenous dose of 2 mg/kg as a 5-minute intravenous infusion had no effect on the QT, PR or QRS intervals.

12.3 Pharmacokinetics

The mean (CV%) Cmax and AUC of Sulfa-Bleu (Methylene Blue) 2,917 ng/mL (39%) and 13977 ng.hr/mL (21%) following a 2 mg/kg dose administered as a 5-minute intravenous infusion.

Distribution

The mean± standard deviation steady state volume of distribution of a 2 mg/kg dose of Sulfa-Bleu (Methylene Blue) was 255 L ± 58. The mean plasma protein binding of Sulfa-Bleu (Methylene Blue) is approximately 94% in vitro. Sulfa-Bleu (Methylene Blue) exhibits concentration-dependent partitioning into blood cells in vitro. The blood-to-plasma ratio was 5.1±2.8 at 5 minutes from the start of a 2 mg/kg dose administered as a 5-minute intravenous infusion and reached a plateau of 0.6 at 4 hours in a clinical study. Sulfa-Bleu (Methylene Blue) is a substrate for the P-glycoprotein (P-gp, ABCB1) transporter, but not for BCRP or OCT2 in vitro.

Elimination

Sulfa-Bleu (Methylene Blue) has a half-life of approximately 24 hours.

Metabolism

Sulfa-Bleu (Methylene Blue) is metabolized by CYPs 1A2, 2C19 and 2D6 in vitro; however, the predominant in vitro pathway appears to be UGT-mediated conjugation by multiple UGT enzymes, including UGT1A4 and UGT1A9.

Azure B, which is a minor impurity in Sulfa-Bleu (Methylene Blue), is also formed in humans as a metabolite of Sulfa-Bleu (Methylene Blue), with an overall drug/metabolite AUC ratio of greater than 6:1. Azure B has 8-fold lower potency than Sulfa-Bleu (Methylene Blue).

Excretion

Approximately 40% of Sulfa-Bleu (Methylene Blue) is excreted in to the urine unchanged.

Drug Interaction Studies

The clinical relevance of in vitro inhibition or induction of the metabolizing enzymes and transporter systems described below is unknown, but it cannot be excluded that the systemic exposure of medicinal products being substrates for these enzymes or transporter systems may be affected with concomitant administration with Sulfa-Bleu (Methylene Blue) Injection.

Cytochrome P450

Sulfa-Bleu (Methylene Blue) inhibits CYP isozymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5 in vitro. Possible time-dependent inhibition of CYP2C9, CYP2D6 and CYP3A4/5 (testosterone as substrate) was also observed in vitro. Sulfa-Bleu (Methylene Blue) induces CYP1A2, but does not induce CYP2B6 or CYP3A4 in vitro.

Glucuronosyltransferase

Sulfa-Bleu (Methylene Blue) inhibits UGT1A9 and UGT1A4 in in vitro, but did not significantly inhibit UGTs 1A1, 1A3, 1A6, 2B7 or 2B15.

Transporter Interactions

Sulfa-Bleu (Methylene Blue) is both a substrate for and an inhibitor of P-gp, but is not a substrate for BCRP or OCT2 in vitro. Sulfa-Bleu (Methylene Blue) is not a significant inhibitor of BCRP, OAT1, OAT3, OAT1B1 or OAT1B3 in vitro. Sulfa-Bleu (Methylene Blue) inhibits OCT2, MATE1 and MATE2-K in vitro. The OCT2/MATE pathway for renal transport is reported to play a significant role in the elimination of several substances, including metformin, cimetidine, acyclovir and creatinine

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year carcinogenicity study, rats were administered oral doses of Sulfa-Bleu (Methylene Blue) at 5, 25, or 50 mg/kg. Sulfa-Bleu (Methylene Blue) caused pancreatic islet adenomas or carcinomas (combined) in male rats. In a two-year year carcinogenicity study, mice were administered oral doses of Sulfa-Bleu (Methylene Blue) at 2.5, 12.5, or 25 mg/kg. There were no drug-related neoplastic findings in mice.

Sulfa-Bleu (Methylene Blue) was genotoxic in gene mutation assays in bacteria (Ames test), and in an in vitro sister chromatid exchange test and an in vitro chromosomal aberration test in Chinese hamster ovary (CHO) cells. Sulfa-Bleu (Methylene Blue) was negative for micronucleus induction in bone marrow or peripheral blood collected from mice treated with Sulfa-Bleu (Methylene Blue).

Fertility studies with Sulfa-Bleu (Methylene Blue) have not been conducted. In vitro, Sulfa-Bleu (Methylene Blue) reduced motility of human sperm in a concentration dependent manner.

14 CLINICAL STUDIES

14.1 Treatment of Acquired Methemoglobinemia

The efficacy of Sulfa-Bleu (Methylene Blue) was assessed on the basis of a methemoglobin decrease of at least 50% within 1 hour after intravenous administration of 1 – 2 mg/kg Sulfa-Bleu (Methylene Blue) (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 Sulfa-Bleu (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 Sulfa-Bleu (Methylene Blue) class product.

In a combined analysis of all 47 patients treated intravenously with Sulfa-Bleu (Methylene Blue) (or a bioequivalent formulation) or with another Sulfa-Bleu (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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Sulfa-Bleu (Methylene Blue) is supplied in 10 mL single-dose ampules. Each 10 mL ampule contains 50 mg of Sulfa-Bleu (Methylene Blue) as a clear dark blue solution. A box contains five ampules placed in a tray.

Box of 5 ampules: NDC 0517-0374-05

Storage:

Store at 20°C to 25°C (68°F to 77°F).

Any unused product or waste material should be disposed of in accordance with local practice.

Do not refrigerate or freeze.

Keep the ampule in the original package to protect from light.

17 PATIENT COUNSELING INFORMATION

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome, especially with concomitant use of serotonergic agents such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur after treatment with Sulfa-Bleu (Methylene Blue) : changes in mental status, autonomic instability, or neuromuscular symptoms with or without gastrointestinal symptoms .

Pregnancy

Advise pregnant women of the potential risk to the fetus with the use of Sulfa-Bleu (Methylene Blue) during pregnancy .

Breastfeeding

Advise patients to discontinue breast-feeding for up to 8 days after treatment with Sulfa-Bleu (Methylene Blue) .

Driving and Using Machines

Advise patients to avoid driving and use of machines during treatment with Sulfa-Bleu (Methylene Blue). Driving can be affected as a result of a confusional state, dizziness and possible eye disturbances .

Phototoxicity

Advise patients to take protective measures against exposure to light, because phototoxicity may occur after administration of Sulfa-Bleu (Methylene Blue) .

Skin and Body Fluid Blue Discoloration

Advise patients that Sulfa-Bleu (Methylene Blue) may cause a blue discoloration of the skin and body fluids .

Manufactured for:

PROVEPHARM SAS

22 rue Marc Donadille

13013 Marseille, France

Manufactured by:

CENEXI

52 rue Marcel et Jacques Gaucher

94120 Fontenay sous Bois, FRANCE

Distributed by:

American Regent

Shirley, NY

Questions? : 1-800-734-9236

4/2016

[controlled part number code]

Principal Display Panel - 5 mg Ampule Label

NDC 0517-0374-01 28039135 Rev 4/16

Sulfa-Bleu (Methylene Blue)

(methylene blue) Injection, 0.5%

50 mg/10 mL (5 mg/mL)

Intravenous use only

Single dose ampule - RX only

Discard unused portion

Manufacturer by:

CENEXI

Distributed by:

AMERICAN REGENT, INC

Shirley, NY 19967

Principal Display Panel - 5 mg Carton Label

NDC 0517-0374-05 5 ampules

Sulfa-Bleu (Methylene Blue)

(methylene blue) Injection, 0.5%

50 mg/10 mL (5 mg/mL)

Intravenous use only - For slow intravenous injection.

10 mL - Single dose ampule -

Discard unused portion

Rx only

Distributed by:

AMERICAN

REGENT

Shirley, NY 11967

Patented: US 8,765,942; US 9,227,945

Sulfacetamide Sodium:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Sulfa-Bleu (Sulfacetamide Sodium) reviews

DESCRIPTION

Sulfa-Bleu ^® ophthalmic suspension is a sterile, topical anti-inflammatory/anti-infective combination product for ophthalmic use.

Structural Formulas

MW=254.24 C₈H₉N₂NaO₃S·H₂O MW=402.49 C₂₃H₃₀O₆

Structural Formulas

Chemical Names

Sulfa-Bleu (Sulfacetamide Sodium) sodium: N-sulfanilylacetamide monosodium salt monohydrate.

Prednisolone acetate: 11ß, 17, 21-trihydroxypregna-1, 4-diene-3, 20-dione 21-acetate.

Each mL of Sulfa-Bleu (Sulfacetamide Sodium) ^® ophthalmic suspension contains:

Actives: Sulfa-Bleu (Sulfacetamide Sodium) sodium 10%, prednisolone acetate (microfine suspension) 0.2%.

Inactives: benzalkonium chloride (0.004%); edetate disodium; polysorbate 80; polyvinyl alcohol 1.4%; potassium phosphate, monobasic; purified water; sodium phosphate, dibasic; sodium thiosulfate; hydrochloric acid and/or sodium hydroxide to adjust pH (6.6 to 7.2).

CLINICAL PHARMACOLOGY

Corticosteroids suppress the inflammatory response to a variety of agents and they probably delay or slow healing. Since corticosteroids may inhibit the body's defense mechanism against infection, a concomitant antibacterial drug may be used when this inhibition is considered to be clinically significant in a particular case.

When a decision to administer both a corticosteroid and an antibacterial is made, the administration of such drugs in combination has the advantage of greater patient compliance and convenience, with the added assurance that the appropriate dosage of both drugs is administered. When both types of drugs are in the same formulation, compatibility of ingredients is assured and the correct volume of drug is delivered and retained. The relative potency of corticosteroids depends on the molecular structure, concentration and release from the vehicle.

Microbiology

Sulfa-Bleu (Sulfacetamide Sodium) sodium exerts a bacteriostatic effect against susceptible bacteria by restricting the synthesis of folic acid required for growth through competition with p-aminobenzoic acid.

Some strains of these bacteria may be resistant to Sulfa-Bleu (Sulfacetamide Sodium) or resistant strains may emerge in vivo.

The anti-infective component in these products is included to provide action against specific organisms susceptible to it. Sulfa-Bleu (Sulfacetamide Sodium) sodium is active in vitro against susceptible strains of the following microorganisms: Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus (viridans group), Haemophilus influenzae, Klebsiella species, and Enterobacter species. This product does not provide adequate coverage against: Neisseria species, Pseudomonas species, and Serratia marcescens.

INDICATIONS AND USAGE

Sulfa-Bleu (Sulfacetamide Sodium) ^® ophthalmic suspension is a steroid/anti-infective combination drug indicated for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists.

Ocular corticosteroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe where the inherent risk of corticosteroid use in certain infective conjunctivitides is accepted to obtain diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns or penetration of foreign bodies.

The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye.

The particular antibacterial drug in this product is active against the following common bacterial eye pathogens: Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus (viridans group), Haemophilus influenzae, Klebsiella species, and Enterobacter species. This product does not provide adequate coverage against: Neisseria species, Pseudomonas species, and Serratia marcescens.

A significant percentage of staphylococcal isolates are completely resistant to sulfa drugs.

CONTRAINDICATIONS

Sulfa-Bleu (Sulfacetamide Sodium) ^® ophthalmic suspension is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures.

Sulfa-Bleu (Sulfacetamide Sodium) ^® ophthalmic suspension is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation, to other sulfonamides and to other corticosteroids. (Hypersensitivity to the antimicrobial component occurs at a higher rate than for other components.)

WARNINGS

NOT FOR INJECTION INTO THE EYE.

Prolonged use of corticosteroids may result in posterior subcapsular cataract formation and may increase intraocular pressure in susceptible individuals, resulting in ocular hypertension/glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision.

If the product is used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients. Corticosteroids should be used with caution in the presence of glaucoma. Intraocular pressure should be checked frequently.

The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.

In those diseases causing thinning of the cornea or sclera, perforation has been known to occur with the use of topical corticosteroids.

In acute purulent conditions of the eye, corticosteroids may mask infection or enhance existing infection.

The use of ocular corticosteroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of corticosteroid medication in the treatment of herpes simplex requires great caution.

Prolonged use of Sulfa-Bleu (Sulfacetamide Sodium) ^® ophthalmic suspension may suppress the host response and thus increase the hazard of secondary ocular infections.

Prolonged use of topical anti-bacterial agents may give rise to overgrowth of nonsusceptible organisms including fungi.

A significant percentage of staphylococcal isolates are completely resistant to sulfonamides.

Acute anterior uveitis may occur in susceptible individuals, primarily Blacks.

Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. Sensitization may recur when a sulfonamide is readministered, irrespective of the route of administration.

If signs of hypersensitivity, skin rash, or other serious reactions occur, discontinue use of this preparation. Cross-sensitivity among corticosteroids has been demonstrated.

PRECAUTIONS

General

The initial prescription and renewal of the medication order beyond 20 milliliters of the suspension should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be re-evaluated.

The possibility of fungal infections of the cornea should be considered after prolonged corticosteroid dosing. Fungal cultures should be taken when appropriate.

Use with caution in patients with severe dry eye.

The p-aminobenzoic acid present in purulent exudates competes with sulfonamides and can reduce their effectiveness.

Information for Patients

If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician.

Contact lenses should not be worn during the use of this product.

This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the applicator tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Protect from light. Sulfonamide solutions darken on prolonged standing and exposure to heat and light. Do not use if solution has darkened. Yellowing does not affect activity. Keep out of the reach of children.

Laboratory Tests

Eyelid cultures and tests to determine the susceptibility of organisms to Sulfa-Bleu (Sulfacetamide Sodium) may be indicated if signs and symptoms persist or recur in spite of the recommended course of treatment with Sulfa-Bleu (Sulfacetamide Sodium) ^® ophthalmic suspension.

Drug Interactions

Sulfa-Bleu ^® ophthalmic suspension is incompatible with silver preparations. Local anesthetics related to p-aminobenzoic acid may antagonize the action of the sulfonamides.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Prednisolone has been reported to be noncarcinogenic. Long-term animal studies for carcinogenic potential have not been performed with Sulfa-Bleu (Sulfacetamide Sodium).

One author detected chromosomal nondisjunction in the yeast Saccharomyces cerevisiae following application of Sulfa-Bleu (Sulfacetamide Sodium) sodium. The significance of this finding to topical ophthalmic use of Sulfa-Bleu (Sulfacetamide Sodium) sodium in the human is unknown.

Mutagenic studies with prednisolone have been negative. Studies on reproduction and fertility have not been performed with Sulfa-Bleu (Sulfacetamide Sodium). A long-term chronic toxicity study in dogs showed that high oral doses of prednisolone prevented estrus. A decrease in fertility was seen in male and female rats that were mated following oral dosing with another glucocorticosteroid.

Pregnancy

Teratogenic Effects

Animal reproduction studies have not been conducted with Sulfa-Bleu sodium. Prednisolone has been shown to be teratogenic in rabbits, hamsters, and mice. In mice, prednisolone has been shown to be teratogenic when given in doses 1 to 10 times the human ocular dose. Dexamethasone, hydrocortisone and prednisolone were ocularly applied to both eyes of pregnant mice five times per day on days 10 through 13 of gestation. A significant increase in the incidence of cleft palate was observed in the fetuses of the treated mice. There are no adequate well-controlled studies in pregnant women dosed with corticosteroids.

Kernicterus may be precipitated in infants by sulfonamides being given systemically during the third trimester of pregnancy. It is not known whether Sulfa-Bleu (Sulfacetamide Sodium) sodium can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity.

Sulfa-Bleu (Sulfacetamide Sodium) ^® ophthalmic suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Systemically administered sulfonamides are capable of producing kernicterus in infants of lactating women. Because of the potential for serious adverse reactions in nursing infants from Sulfa-Bleu (Sulfacetamide Sodium) sodium and prednisolone acetate ophthalmic suspensions, a decision should be made whether to discontinue nursing or to discontinue the medication.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 6 years have not been established.

ADVERSE REACTIONS

The following adverse reactions have been identified during use of Sulfa-Bleu (Sulfacetamide Sodium) ^® ophthalmic suspension. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions have occurred with corticosteroid/antibacterial combination drugs which can be attributed to the corticosteroid component, the antibacterial component, or the combination.

Reactions occurring with Sulfa-Bleu (Sulfacetamide Sodium) ^® ophthalmic suspension include: cataract, dizziness, eye discharge, eyelid edema, eyelid erythema, eye irritation, eye pain, eye pruritus, and hypersensitivity including rash, skin pruritus, urticaria, ocular hyperemia, and visual disturbance (blurry vision).

Reactions occurring most often from the presence of the antibacterial ingredient are allergic sensitizations. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.

The reactions due to the corticosteroid component in decreasing order of frequency are: delayed wound healing, elevation of intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage, and posterior subcapsular cataract formation.

Although systemic effects are extremely uncommon, there have been rare occurrences of systemic hypercorticoidism after use of topical corticosteroids.

Corticosteroid-containing preparations can also cause acute anterior uveitis or perforation of the globe. Mydriasis, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids.

Secondary Infection

The development of secondary infection has occurred after use of combinations containing corticosteroids and antibacterials. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of corticosteroid. The possibility of fungal invasion must be considered in any persistent corneal ulceration where corticosteroid treatment has been used.

Secondary bacterial ocular infection following suppression of host responses also occurs.

DOSAGE AND ADMINISTRATION

SHAKE WELL BEFORE USING. Two drops should be instilled into the conjunctival sac every four hours during the day and at bedtime.

Not more than 20 milliliters should be prescribed initially, and the prescription should not be refilled without further evaluation as outlined in PRECAUTIONS above.

Sulfa-Bleu (Sulfacetamide Sodium) ^® dosage may be reduced, but care should be taken not to discontinue therapy prematurely. In chronic conditions, withdrawal of treatment should be carried out by gradually decreasing the frequency of application.

If signs and symptoms fail to improve after two days, the patient should be re-evaluated.

HOW SUPPLIED

Sulfa-Bleu (Sulfacetamide Sodium) ^® (sulfacetamide sodium–prednisolone acetate ophthalmic suspension, USP) is supplied sterile in opaque white LDPE plastic bottles and white dropper tips with white high impact polystyrene (HIPS) caps as follows:

• 5 mL in 10 mL bottle - NDC 11980-022-05
• 10 mL in 15 mL bottle - NDC 11980-022-10

Note: Shake well before using.

Storage: Store at 8°-24°C (46°-75°F) in an upright position. PROTECT FROM LIGHT. Protect from freezing.

Sulfonamide solutions darken on prolonged standing and exposure to heat and light. Do not use if solution has darkened. Yellowing does not affect activity.

KEEP OUT OF REACH OF CHILDREN.

Revised: 07/2017

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