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DRUGS & SUPPLEMENTS
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Desmoidpillen
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Desmoidpillen uses
- 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
WARNING: SEROTONIN SYNDROME WITH CONCOMITANT USE OF SEROTONERGIC DRUGS
Desmoidpillen may cause serious or fatal serotonergic syndrome when used in combination with serotonergic drugs. Avoid concomitant use of Desmoidpillen with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors ( 5.1, 7.1).
1 INDICATIONS AND USAGE
Desmoidpillen 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.
Desmoidpillen (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 Desmoidpillen. Do not administer Desmoidpillen subcutaneously.
- Monitor vital signs, electrocardiogram and methemoglobin levels during treatment with Desmoidpillen and through resolution of methemoglobinemia.
- Administer Desmoidpillen 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 Desmoidpillen 1 mg/kg may be given one hour after the first dose.
- If methemoglobinemia does not resolve after 2 doses of Desmoidpillen, consider initiating alternative interventions for treatment of methemoglobinemia.
2.2 Preparation and Storage
Each mL of Desmoidpillen contains 5 mg Desmoidpillen
Each 10 mL ampule of Desmoidpillen contains 50 mg Desmoidpillen.
Desmoidpillen 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 Desmoidpillen.
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
Desmoidpillen is contraindicated in the following conditions:
- Severe hypersensitivity reactions to Desmoidpillen or any other thiazine dye .
- Patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) due to the risk of hemolytic anemia
Desmoidpillen is contraindicated in the following conditions ( 4):
- Severe hypersensitivity to Desmoidpillen
- 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 Desmoidpillen, treat the allergic reaction, and monitor until signs and symptoms resolve
- Lack of Effectiveness: Consider alternative treatments if there is no resolution of methemoglobinemia after 2 doses ( 2.1, 5.3)
- Hemolytic Anemia: Discontinue Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen with serotonergic drugs.
Patients treated with Desmoidpillen should be monitored for the emergence of serotonin syndrome. If symptoms of serotonin syndrome occur, discontinue use of Desmoidpillen, 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 Desmoidpillen .
5.2 Hypersensitivity
Anaphylactic reactions to Desmoidpillen class products have been reported. Patients treated with Desmoidpillen should be monitored for anaphylaxis. If anaphylaxis or other severe hypersensitivity reactions should occur, discontinue use of Desmoidpillen and initiate supportive treatment. Desmoidpillen is contraindicated in patients who have experienced anaphylaxis or other severe hypersensitivity reactions to a Desmoidpillen class product in the past.
5.3 Lack of Effectiveness
Methemoglobinemia may not resolve or may rebound after response to treatment with Desmoidpillen in patients with methemoglobinemia due to aryl amines such as aniline or sulfa drugs such as dapsone. Monitor response to therapy with Desmoidpillen through resolution of methemoglobinemia. If methemoglobinemia does not respond to 2 doses of Desmoidpillen or if methemoglobinemia rebounds after a response, consider additional treatment options .
Patients with glucose-6-phosphate dehydrogenase deficiency may not reduce Desmoidpillen to its active form in vivo. Desmoidpillen 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 Desmoidpillen. 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 Desmoidpillen. The anemia may require red blood cell transfusions. . Use the lowest effective number of doses of Desmoidpillen to treat methemoglobinemia. Discontinue Desmoidpillen and consider alternative treatments of methemoglobinemia if severe hemolysis occurs.
Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with Desmoidpillen may result in severe hemolysis and severe anemia. Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen, 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 Desmoidpillen class products. If Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen have resolved.
5.7 Interference with Laboratory Tests
Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen.
| Adverse Reaction | Any Grade TEAE (n=82) | Moderate- Severe TEAE (n=82) | ||
| Pain in extremity | 69 | 84% | 46 | 56% |
| Chromaturia | 61 | 74% | 0 | |
| Dysgeusia | 16 | 20% | 1 | 1% |
| Feeling hot | 14 | 17% | 5 | 6% |
| Dizziness | 13 | 16% | 4 | 5% |
| Hyperhidrosis | 11 | 13% | 2 | 2% |
| Nausea | 11 | 13% | 2 | 2% |
| Skin discoloration | 11 | 13% | 0 | |
| Headache | 8 | 10% | 6 | 7% |
| Musculoskeletal pain | 7 | 9% | 0 | |
| Paresthesia oral | 7 | 9% | 0 | |
| Paresthesia | 7 | 9% | 0 | |
| Infusion site pain | 5 | 6% | 1 | 1% |
| Feeling cold | 5 | 6% | 0 | |
| Pallor | 4 | 5% | 0 | |
| Dermatitis contact | 4 | 5% | 0 | |
| Syncope | 3 | 4% | 3 | 4% |
| Influenza like illness | 3 | 4% | 1 | 1% |
| Pruritus | 3 | 4% | 1 | 1% |
| Anxiety | 3 | 4% | 0 | |
| Decreased appetite | 3 | 4% | 0 | |
| Chest discomfort | 3 | 4% | 0 | |
| Back pain | 2 | 2% | 2 | 2% |
| Cold sweat | 2 | 2% | 1 | 1% |
| Dizziness postural | 2 | 2% | 1 | 1% |
| Muscle spasms | 2 | 2% | 1 | 1% |
| Presyncope | 2 | 2% | 1 | 1% |
| Vomiting | 2 | 2% | 1 | 1% |
| Arthralgia | 2 | 2% | 1 | 1% |
| Chills | 2 | 2% | 0 | |
| Diarrhea | 2 | 2% | 0 | |
| Discomfort | 2 | 2% | 0 | |
| Dyspnea | 2 | 2% | 0 | |
| Erythema | 2 | 2% | 0 | |
| Hypoesthesia oral | 2 | 2% | 0 | |
| Infusion site discomfort | 2 | 2% | 0 | |
| Limb discomfort | 2 | 2% | 0 | |
| Oral discomfort | 2 | 2% | 0 | |
| Catheter site pain | 2 | 2% | 0 | |
| Ecchymosis | 2 | 2% | 0 | |
Other adverse reactions reported to occur following administration of Desmoidpillen 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 Desmoidpillen with medicinal products that enhance serotonergic transmission including SSRIs, 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 Desmoidpillen may be involved. In addition, in vitro studies cannot rule out the potential involvement of CYP 2D6 inhibition by Desmoidpillen. If the intravenous use of Desmoidpillen 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
Desmoidpillen 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
Desmoidpillen may cause fetal harm when administered to a pregnant woman. Intra-amniotic injection of pregnant women with a Desmoidpillen class product during the second trimester was associated with neonatal intestinal atresia and fetal death. Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen to a pregnant woman at term, observe the newborn for these adverse reactions and institute supportive care.
Data
Animal Data
Desmoidpillen 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 Desmoidpillen, 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.
Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen .
8.4 Pediatric Use
The safety and effectiveness of Desmoidpillen have been established in pediatric patients. Use of Desmoidpillen is supported by two retrospective case series that included 2 pediatric patients treated with Desmoidpillen and 12 treated with another Desmoidpillen 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 Desmoidpillen and 5 treated with another Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen.
8.7 Hepatic Impairment
Desmoidpillen 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 Desmoidpillen.
10 OVERDOSAGE
Hypotension, wheezing and reduced oxygenation have been reported in patients who received Desmoidpillen class products in single doses of 3 mg/kg or more.
Administration of large intravenous doses (cumulative dose ≥ 7 mg/kg ) of a Desmoidpillen 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 Desmoidpillen class product caused severe intravascular hemolysis, hyperbilirubinemia and death.
In case of overdose of Desmoidpillen, 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
Desmoidpillen is an oxidation-reduction agent. Desmoidpillen (methylene blue) is a sterile solution intended for intravenous administration. Each Desmoidpillen, 10 mL ampule contains 50 mg Proveblue ® Desmoidpillen and water for injection q.s. Each mL of solution contains 5 mg Desmoidpillen and water for injection q.s.
Desmoidpillen is 3,7-bis(dimethylamino)phenothiazin-5-ium, chloride. The molecular formula of Desmoidpillen is C 16H 18ClN 3S and its molecular weight is 319.86 g/mol. Its structural formula is:
Desmoidpillen 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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Desmoidpillen is a water soluble thiazine dye that promotes a non-enyzmatic redox conversion of metHb to hemoglobin. In situ, Desmoidpillen is first converted to leucomethylene blue 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 Desmoidpillen speeds up the in vivo conversion of methemoglobin to hemoglobin. Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen 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 Desmoidpillen was 255 L ± 58. The mean plasma protein binding of Desmoidpillen is approximately 94% in vitro. Desmoidpillen 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. Desmoidpillen is a substrate for the P-glycoprotein (P-gp, ABCB1) transporter, but not for BCRP or OCT2 in vitro.
Elimination
Desmoidpillen has a half-life of approximately 24 hours.
Metabolism
Desmoidpillen 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 Desmoidpillen, is also formed in humans as a metabolite of Desmoidpillen, with an overall drug/metabolite AUC ratio of greater than 6:1. Azure B has 8-fold lower potency than Desmoidpillen.
Excretion
Approximately 40% of Desmoidpillen 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 Desmoidpillen Injection.
Cytochrome P450
Desmoidpillen 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. Desmoidpillen induces CYP1A2, but does not induce CYP2B6 or CYP3A4 in vitro.
Glucuronosyltransferase
Desmoidpillen inhibits UGT1A9 and UGT1A4 in in vitro, but did not significantly inhibit UGTs 1A1, 1A3, 1A6, 2B7 or 2B15.
Transporter Interactions
Desmoidpillen is both a substrate for and an inhibitor of P-gp, but is not a substrate for BCRP or OCT2 in vitro. Desmoidpillen is not a significant inhibitor of BCRP, OAT1, OAT3, OAT1B1 or OAT1B3 in vitro. Desmoidpillen 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 Desmoidpillen at 5, 25, or 50 mg/kg. Desmoidpillen caused pancreatic islet adenomas or carcinomas (combined) in male rats. In a two-year year carcinogenicity study, mice were administered oral doses of Desmoidpillen at 2.5, 12.5, or 25 mg/kg. There were no drug-related neoplastic findings in mice.
Desmoidpillen 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. Desmoidpillen was negative for micronucleus induction in bone marrow or peripheral blood collected from mice treated with Desmoidpillen.
Fertility studies with Desmoidpillen have not been conducted. In vitro, Desmoidpillen reduced motility of human sperm in a concentration dependent manner.
14 CLINICAL STUDIES
14.1 Treatment of Acquired Methemoglobinemia
The efficacy of Desmoidpillen was assessed on the basis of a methemoglobin decrease of at least 50% within 1 hour after intravenous administration of 1 – 2 mg/kg Desmoidpillen (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 Desmoidpillen 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 Desmoidpillen class product.
In a combined analysis of all 47 patients treated intravenously with Desmoidpillen (or a bioequivalent formulation) or with another Desmoidpillen 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
Desmoidpillen is supplied in 10 mL single-dose ampules. Each 10 mL ampule contains 50 mg of Desmoidpillen 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 Desmoidpillen : 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 Desmoidpillen during pregnancy .
Breastfeeding
Advise patients to discontinue breast-feeding for up to 8 days after treatment with Desmoidpillen .
Driving and Using Machines
Advise patients to avoid driving and use of machines during treatment with Desmoidpillen. 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 Desmoidpillen .
Skin and Body Fluid Blue Discoloration
Advise patients that Desmoidpillen 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
Desmoidpillen
(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
Desmoidpillen
(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
Desmoidpillen pharmaceutical active ingredients containing related brand and generic drugs:
Desmoidpillen available forms, composition, doses:
Desmoidpillen destination | category:
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References
- Dailymed."PROVAYBLUE (METHYLENE BLUE) INJECTION [AMERICAN REGENT]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- Dailymed."METHYLENE BLUE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- "methylene blue". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
Frequently asked Questions
Can i drive or operate heavy machine after consuming Desmoidpillen?Depending on the reaction of the Desmoidpillen after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Desmoidpillen not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Desmoidpillen addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Review
sdrugs.com conducted a study on Desmoidpillen, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Desmoidpillen consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.Visitor reports
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The information was verified by Dr. Rachana Salvi, MD Pharmacology