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0 6.2 Post-Marketing Experiences The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.
Body as a whole : diffuse pain, chest pain, radiation recall phenomenon.
Cardiovascular : atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.
Cutaneous : very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported. Cases of permanent alopecia have been reported.
Gastrointestinal : abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported.
Hematologic : bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with TAXOTERE when used in combination with other chemotherapy agents and/or radiotherapy.
Hypersensitivity : rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.
Hepatic : rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.
Neurologic : confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug.
Ophthalmologic : conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of cystoid macular edema (CME) have been reported in patients treated with TAXOTERE.
Hearing : rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.
Respiratory : dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.
Renal : renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.
Metabolism and nutrition disorders : cases of hyponatremia have been reported. BACK TO TOP 7. DRUG INTERACTIONS Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.
In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of TAXOTERE and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with TAXOTERE, close monitoring for toxicity and a TAXOTERE dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3) ] . 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see ‘ Warnings and Precautions ‘ section ]
Based on its mechanism of action and findings in animals, TAXOTERE can cause fetal harm when administered to a pregnant woman. If TAXOTERE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with TAXOTERE.
TAXOTERE can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m 2 basis), administered during the period of organogenesis, have shown that TAXOTERE is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity. 8.3 Nursing Mothers It is not known whether docetaxel is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from TAXOTERE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The alcohol content of TAXOTERE Injection should be taken into account when given to pediatric patients [see Warnings and Precautions (5.11) ] .
The efficacy of TAXOTERE in pediatric patients as monotherapy or in combination has not been established. The overall safety profile of TAXOTERE in pediatric patients receiving monotherapy or TCF was consistent with the known safety profile in adults.
TAXOTERE has been studied in a total of 289 pediatric patients: 239 in 2 trials with monotherapy and 50 in combination treatment with cisplatin and 5-fluoruracil (TCF). TAXOTERE Monotherapy
TAXOTERE monotherapy was evaluated in a dose-finding phase 1 trial in 61 pediatric patients (median age 12.5 years, range 1–22 years) with a variety of refractory solid tumors. The recommended dose was 125 mg/m 2 as a 1-hour intravenous infusion every 21 days. The primary dose limiting toxicity was neutropenia.
The recommended dose for TAXOTERE monotherapy was evaluated in a phase 2 single-arm trial in 178 pediatric patients (median age 12 years, range 1–26 years) with a variety of recurrent/refractory solid tumors. Efficacy was not established with tumor response rates ranging from one complete response (CR) (0.6%) in a patient with undifferentiated sarcoma to four partial responses (2.2%) seen in one patient each with Ewing Sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma. TAXOTERE in Combination
TAXOTERE was studied in combination with cisplatin and 5-fluorouracil (TCF) versus cisplatin and 5-fluorouracil (CF) for the induction treatment of nasopharyngeal carcinoma (NPC) in pediatric patients prior to chemoradiation consolidation. Seventy-five patients (median age 16 years, range 9 to 21 years) were randomized (2:1) to TAXOTERE (75 mg/m 2 ) in combination with cisplatin (75 mg/m 2 ) and 5-fluorouracil (750 mg/m 2 ) (TCF) or to cisplatin (80 mg/m 2 ) and 5-fluorouracil (1000 mg/m 2 /day) (CF). The primary endpoint was the CR rate following induction treatment of NPC. One patient out of 50 in the TCF group (2%) had a complete response while none of the 25 patients in the CF group had a complete response. Pharmacokinetics:
Pharmacokinetic parameters for docetaxel were determined in 2 pediatric solid tumor trials. Following docetaxel administration at 55 mg/m 2 to 235 mg/m 2 in a 1-hour intravenous infusion every 3 weeks in 25 patients aged 1 to 20 years (median 11 years), docetaxel clearance was 17.3±10.9 L/h/m 2 .
Docetaxel was administered in combination with cisplatin and 5-fluorouracil (TCF), at dose levels of 75 mg/m 2 in a 1-hour intravenous infusion day 1 in 28 patients aged 10 to 21 years (median 16 years, 17 patients were older than 16). Docetaxel clearance was 17.9±8.75 L/h/m 2 , corresponding to an AUC of 4.20±2.57 μg.h/mL.
In summary, the body surface area adjusted clearance of docetaxel monotherapy and TCF combination in children were comparable to those in adults [see Clinical Pharmacology (12.3) ] . 8.5 Geriatric Use In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients. Non-Small Cell Lung Cancer
In a study conducted in chemotherapy-naïve patients with NSCLC (TAX326), 148 patients (36%) in the TAXOTERE+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the TAXOTERE+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with TAXOTERE+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with TAXOTERE+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively).
When TAXOTERE was combined with carboplatin for the treatment of chemotherapy-naïve, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with TAXOTERE+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin. Prostate Cancer
Of the 333 patients treated with TAXOTERE every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with TAXOTERE every three weeks, the following treatment emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively. Breast Cancer
In the adjuvant breast cancer trial (TAX316), TAXOTERE in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients. Gastric Cancer
Among the 221 patients treated with TAXOTERE in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored. Head and Neck Cancer
Among the 174 and 251 patients who received the induction treatment with TAXOTERE in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively.
These clinical studies of TAXOTERE in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients. 8.6 Hepatic Impairment Patients with bilirubin >ULN should not receive TAXOTERE. Also, patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN should not receive TAXOTERE [see Boxed Warning , Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] .
The alcohol content of TAXOTERE Injection should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions (5.11) ] . BACK TO TOP 10. OVERDOSAGE There is no known antidote for TAXOTERE overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.
In two reports of overdose, one patient received 150 mg/m 2 and the other received 200 mg/m 2 as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.
In mice, lethality was observed following single intravenous doses that were ≥154 mg/kg (about 4.5 times the human dose of 100 mg/m 2 on a mg/m 2 basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m 2 basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m 2 on a mg/m 2 basis) and was associated with abnormal mitosis and necrosis of multiple organs. BACK TO TOP 11. DESCRIPTION Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N- tert -butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate. Docetaxel has the following structural formula:
Docetaxel is a white to almost-white powder with an empirical formula of C 43 H 53 NO 14 • 3H 2 O, and a molecular weight of 861.9. It is highly lipophilic and practically insoluble in water. One-vial TAXOTERE (Injection Concentrate)
TAXOTERE (docetaxel) Injection Concentrate is a sterile, non-pyrogenic, pale yellow to brownish-yellow solution at 20 mg/mL concentration.
Each mL contains 20 mg docetaxel (anhydrous) in 0.54 grams polysorbate 80 and 0.395 grams dehydrated alcohol solution.
TAXOTERE is available in single use vials containing 20 mg (1 mL) or 80 mg (4 mL) docetaxel (anhydrous).
TAXOTERE Injection Concentrate requires NO prior dilution with a diluent and is ready to add to the infusion solution. 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use. 12.3 Human Pharmacokinetics Absorption: The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 20 mg/m 2 to 115 mg/m 2 in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70 mg/m 2 to 115 mg/m 2 with infusion times of 1 to 2 hours. Docetaxel’s pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hr, respectively. Mean total body clearance was 21 L/h/m 2 . Distribution: The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to α 1 -acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel. Metabolism: In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 [see Drug Interactions (7) ] . Elimination: A study of 14 C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert -butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug. Effect of Age: A population pharmacokinetic analysis was carried out after TAXOTERE treatment of 535 patients dosed at 100 mg/m 2 . Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel were not influenced by age. Effect of Gender: The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of docetaxel. Hepatic Impairment: The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment (AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients. Patients with combined abnormalities of transaminase and alkaline phosphatase should not be treated with TAXOTERE. Patients with severe hepatic impairment have not been studied . [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6) ] Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m 2 to 90 mg/m 2 was similar to that of European/American populations dosed at 100 mg/m 2 , suggesting no significant difference in the elimination of docetaxel in the two populations. Effect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of docetaxel was investigated in 7 cancer patients. Patients were randomized to receive either docetaxel (100 mg/m 2 intravenous) alone or docetaxel (10 mg/m 2 intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of docetaxel was increased 2.2-fold and its clearance was reduced by 49% when docetaxel was co-administration with ketoconazole [see Dosage and Administration (2.7) and Drug-Drug Interactions (7) ] . Effect of Combination Therapies: Dexamethasone: Docetaxel total body clearance was not modified by pretreatment with dexamethasone. Cisplatin: Clearance of docetaxel in combination therapy with cisplatin was similar to that previously observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in combination therapy with docetaxel was similar to that observed with cisplatin alone. Cisplatin and Fluorouracil: The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumors had no influence on the pharmacokinetics of each individual drug. Prednisone: A population pharmacokinetic analysis of plasma data from 40 patients with hormone-refractory metastatic prostate cancer indicated that docetaxel systemic clearance in combination with prednisone is similar to that observed following administration of docetaxel alone. Cyclophosphamide and Doxorubicin: A study was conducted in 30 patients with advanced breast cancer to determine the potential for drug-drug-interactions between docetaxel (75 mg/m 2 ), doxorubicin (50 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ) when administered in combination. The coadministration of docetaxel had no effect on the pharmacokinetics of doxorubicin and cyclophosphamide when the three drugs were given in combination compared to coadministration of doxorubicin and cyclophosphamide only. In addition, doxorubicin and cyclophosphamide had no effect on docetaxel plasma clearance when the three drugs were given in combination compared to historical data for docetaxel monotherapy.

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Pulmicort Respules (Budesonide Inhalation Suspension) – updated on RxList

<h1>Pulmicort Respules (Budesonide Inhalation Suspension) – updated on RxList</h1>

Pulmicort Respules (Budesonide Inhalation Suspension) – updated on RxList

Skin and subcutaneous tissue disorders contact dermatitis , eczema , pustular rash, pruritus ,
The incidence of reported adverse events was similar between the 447 PULMICORT RESPULES-treated (mean total daily dose 0.5 to 1 mg) a
Endocrine disorders : symptoms of hypocorticism and hypercorticism [see WARNINGS AND PRECAUTIONS
Eye disorders : cataracts, glaucoma, increased intraocular pressure [see WARNINGS AND PRECAUTIONS
General disorders and administration site conditions fever ,
Immune system disorders : immediate and delayed hypersensitivity reactions including, anaphylaxis, angioedema , bronchospasm, rash, contact dermatitis , and urticaria [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS
Infection and Infestation sinusitis , pharyngitis ,
Musculoskeletal and connective tissue disorders avascular necrosis of the femoral head, osteoporosis
Nervous system disorders :
Psychiatric disorders : psychiatric symptoms including psychosis , depression , aggressive reactions, irritability, nervousness, restlessness, and
Respiratory, thoracic, and mediastinal disorders cough
Skin and subcutaneous tissue disorders :
Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for PULMICORT RESPULES [see WARNINGS AND PRECAUTIONS and Use In Specific Populations , Pediatric Use Inhibitors of Cytoch
The main route of metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole , a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of a CYP3A4 inhibitor may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of PULMICORT RESPULES (budesonide inhalation suspension) with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin , indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY , Pharmacokinetics Warnings &
Included as part of the PRECAUTIONS
In clinical trials with PULMICORT RESPULES (budesonide inhalation suspension) , localized infections with Candida albicans occurred in the mouth and pharynx in some patients. The incidences of localized infections of Candida albicans were similar between the placebo and PULMICORT RESPULES (budesonide inhalation suspension) treatment groups. If these infections develop, they may require treatment with appropriate local or systemic antifungal
Hypersensitivity reactions including anaphylaxis, rash , contact dermatitis , urticaria , angioedema , and bronchospasm have been reported with use of PULMICORT RESPULES. Discontinue PULMICORT RESPULES if such reactions occur [see CONTRAINDICATIONS
Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles , for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases, or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled immunoglobulin ( IG ) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information .) If chicken pox develops, treatment with antiviral
The clinical course of chicken pox or measles infection in patients on inhaled corticosteroids has not been studied. However, a clinical study has examined the immune responsiveness of asthma patients 12 months to 8 years of age who were treated with PULMICORT RESPULES (budesonide inhalation suspension) . An open-label non-randomized clinical study examined the immune responsiveness of varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with PULMICORT RESPULES (budesonide inhalation suspension) 0.25 mg to 1 mg daily (n=151) or noncorticosteroid asthma therapy (n=92) (ie, beta2-agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥ 5.0 (gpELISA value) in response to the vaccination
Inhaled corticosteroids should be used with caution, if at all, in patients with active or tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular
Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic- pituitary -adrenal (HPA)- axis
Patients who have been previously maintained on 20 mg or more per day of prednisone
During this period of HPA-axis suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma , surgery, infection (particularly gastroenteritis ) or other conditions associated with severe electrolyte loss. Although PULMICORT RESPULES (budesonide inhalation suspension) may provide control of asthma symptoms duri
During periods of stress
Lung function (FEV 1 or PEF ), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude , weakness, nausea and vomiting, and hypotension
Transfer of patients from systemic corticosteroid therapy to PULMICORT RESPULES (budesonide inhalation suspension) may unmask allergic or other immunologic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis , conjunctivitis , eosinophilic conditions, eczema, and arthritis [see DOSAGE AND ADMINISTRATION
During withdrawal from oral corticosteroids, patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or pain , lassitude, depression
PULMICORT RESPULES (budesonide inhalation suspension) , will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing PULMICORT RESPULES (budesonide inhalation suspension) . Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT RESPULES (budesonide inhalation suspension) should be observed carefully for any e
Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis , poor nutrition
Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving PULMICORT RESPULES (budesonide inhalation suspension) routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including PULMICORT RESPULES (budesonide inhalation suspension) , each patient should be titrated to his/her lowest effective dose [see Use In Specific Populations, Pediatric Use
Glaucoma, increased intraocular pressure
As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing
In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg- Strauss syndrome, a condition that is often treated with systemic corticosteroids therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Healthcare providers should be alert to eosinophilia , vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship betw
Caution should be exercised when considering the coadministration of PULMICORT RESPULES with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY , Clinical Pharmacokinetics
Patients should be advised that PULMICORT RESPULES (budesonide inhalation suspension) should be administered with a jet nebulizer connected to a compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. Ultrasonic nebulizers are not suitable for the adequate administration of PULMICORT RESPULES (budesonide inhalation suspension) and, therefore, are not recommended. The effects of mixing PULMICORT RESPULES (budesonide inhalation suspension) with other nebulizable medications have not been adequately assessed. PULMICORT RESPULES (budesonide inhalation suspension) should be administered separately in the nebulizer [see DOSAGE AND ADMINISTRATION
Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e. oral) antifungal therapy while still continuing therapy with PULMICORT RESPULES (budesonide inhalation suspension) , but at times therapy with PULMICORT RESPULES (budesonide inhalation suspension) may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see WARNINGS AND PRECAUTIONS
PULMICORT RESPULES (budesonide inhalation suspension) is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2- agonist such as albuterol
Patients should not stop therapy with PULMICORT RESPULES (budesonide inhalation suspension) without physician/provider guidance since symptoms may recur after discontinuation [see WARNINGS AND PRECAUTIONS
Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT RESPULES. Discontinue PULMICORT RESPULES if such reactions occur [see CONTRAINDICATIONS ; WARNINGS AND PRECAUTIONS
Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. If exposure to such a person occurs, and the child has not had chicken pox or been properly vaccinated, a physician should be consulted without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see WARNINGS AND PRECAUTIONS
Patients should be advised that PULMICORT RESPULES (budesonide inhalation suspension) may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to PULMICORT RESPULES (budesonide inhalation suspension) [see WARNINGS AND PRECAUTIONS
Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk [see WARNINGS AND PRECAUTIONS
Patients should be informed that orally inhaled corticosteroids, including PULMICORT RESPULES (budesonide inhalation suspension) , may cause a reduction in growth velocity when administered to pediatric patients. Healthcare professionals should closely follow the growth of children and adolescents taking corticosteroids by any route [see WARNINGS AND PRECAUTIONS
Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered [see WARNINGS AND PRECAUTIONS
See accompanying PATIENT INFORMATION
In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.4 and 0.1 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.2 and 0.06 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis) and in female rats at oral doses up to 50 mcg/kg (approximately 0.4 and 0.1 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.4 and 0.1 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.4 and 0.1 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis). The concurrent reference corticosteroids ( prednisolone and triamcinolone
In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.8 and 0.2 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m²
Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella /microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked lethal test in Drosophila melanogaster , and DNA repair
In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg approximately 0.6 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis. However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg and above approximately 0.2 times than the maximum recommended daily inhalation dose in adults on a mcg/m² basis. No such effects were noted at 5 mcg/kg (approximately 0.04 times the maximum recommended daily inhalation dose in adults on a mcg/m²
– Studies of pregnant women, have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (ie, Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period
These s
As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose in rabbits that was approximately 0.4 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis and at subcutaneous dose that was approximately 4 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis. In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to approximately 2 times the maximum recommended daily inhalation dose in adults on a mcg/m²
Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic , doses suggests that rodents are more prone Nursing
Budesonide, like other corticosteroids, is secreted in human milk. Data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see CLINICAL PHARMACOLOGY , Pharmacokinetics, and Use In Specific Populations, Nursing Mothers
Safety and effectiveness in children six months to 12 months of age has been evaluated but not established. Safety and effectiveness in children 12 months to 8 years of age have been established [see CLINICAL PHARMACOLOGY , Pharmacodynamics, and ADVERSE REACTIONS , Clinical Trials Experience
A 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent /persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg of PULMICORT RESPULES (budesonide inhalation suspension) or placebo once daily. Adrenal-axis function was assessed with an ACTH stimulation test at the beginning and end of the study, and mean changes from baseline in this variable did not indicate adrenal suppression in patients who received PULMICORT RESPULES versus placebo. However, on an individual basis, 7 patients in this study (6 in the PULMICORT RESPULES (budesonide inhalation suspension) treatment arms and 1 in the placebo arm) experienced a shift from having a normal baseline stimulated cortisol level to having a subnormal level at Week 12 [see CLINICAL PHARMACOLOGY , Pharmacodynamics ]. Pneumonia
Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch up”
The growth of pediatric patients receiving inhaled corticosteroids, including PULMICORT RESPULES (budesonide inhalation suspension) , should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks and benefits associated with alternative therapies. To minimize the systemic effects of inhaled corticosteroids, including PULMICORT RESPULES, each patient should be titrated to his/her lowest effective dose [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS Overdosage &
The potential for acute toxic effects following overdose of PULMICORT RESPULES (budesonide inhalation suspension) is low. If inhaled corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism or growth suppression may occur [see WARNINGS AND PRECAUTIONS , Hypercorticism and Adrenal Suppression
In mice, the minimal lethal inhalation dose was 100 mg/kg (approximately 410 and 120 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In rats there were no deaths at an inhalation dose of 68 mg/kg (approximately 550 and 160 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In mice, the minimal oral lethal dose was 200 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In rats, the minimal oral lethal dose was less than 100 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults or and children 12 months to 8 years of age on a mg/m² Hypersensitivity to budesonide or any of the ingredients of PULMICORT RESPULES [see WARNINGS AND PRECAUTIONS , DESCRIPTION and ADVERSE REACTIONS , Post-marketing Experience CLINICAL PHARMACOLOGY Mechanism of Action
Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol thymus assay. The clinical significance of these findings is unknown.
The activity of PULMICORT RESPULES is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.
The precise mechanism of corticosteroid actions on inflammation in asthma is not well known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., , eicosanoids, leukotrienes, and cytokines) involved in allergic- and non-allergic-mediated inflammation. The anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activities and systemic corticosteroid effects over a wide dose range of inhaled budesonide in a variety of formulations and delivery systems including an inhalation-driven, multi-dose dry powder inhaler and the inhalation suspension for nebulization. This is explained by a combination of a relatively high local antiinflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%) and the low potency of metabolites (see ). Pharmacodynamics
The therapeutic effects of conventional doses of orally inhaled budesonide are largely explained by its direct local action on the respiratory tract. To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in adult patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally administered budesonide, even though systemic budesonide exposure was comparable for both treatments, indicating that the inhaled treatment is working locally in the lung. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract.
reatment, although maximum benefit may not be achieved for 4-6 weeks.
Budesonide administered via a dry powder inhaler has been shown in various challenge models (including histamine, methacholine, sodium metabisulfite, and monophosphate) to decrease bronchial hyperresponsiveness in asthmatic patients. The clinical relevance of these models is not certain.
Pre-treatment with budesonide administered as 1600 mcg daily (800 mcg twice daily) via a dry powder inhaler for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV 1 following inhaled challenge. HPA Axis Effects
The effects of PULMICORT RESPULES (budesonide inhalation suspension) on the hypothalamic-pituitary-adrenal (HPA) axis were studied in three, 12-week, double-blind, placebo-controlled studies in 293 pediatric patients, 6 months to 8 years of age, with persistent asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by the short cosyntropin (ACTH) stimulation test, remained intact with PULMICORT RESPULES (budesonide inhalation suspension) treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) receiving a total daily dose of PULMICORT RESPULES equivalent to 0.25 mg (n=5), 0.5 mg (n=5), 1 mg (n=8), or placebo (n=3), the mean change from baseline in ACTH-stimulated cortisol levels showed a decline in peak stimulated cortisol at 12 weeks compared to an increase in the placebo group. These mean differences were not statistically significant compared to placebo. Another 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg of PULMICORT RESPULES (budesonide inhalation suspension) or placebo once daily. A total of 28, 17, and 31 patients in the PULMICORT RESPULES (budesonide inhalation suspension) 0.5 mg, 1 mg, and placebo arms respectively, had an evaluation of serum cortisol levels post-ACTH stimulation both at baseline and at the end of the study. The mean change from baseline to Week 12 ACTH-stimulated minus basal plasma cortisol levels did not indicate adrenal suppression in patients treated with PULMICORT RESPULES versus placebo. However, 7 patients in this study (4 of whom received PULMICORT RESPULES (budesonide inhalation suspension) 0.5 mg, 2 of whom received PULMICORT RESPULES (budesonide inhalation suspension) 1 mg and 1 of whom received placebo) showed a shift from normal baseline stimulated cortisol level ( ≥ 500 nmol/L) to a subnormal level ( 500 nmol/L) at Week 12. In 4 of these patients receiving PULMICORT RESPULES (budesonide inhalation suspension) , the cortisol values were near the cutoff value of 500 nmol/L.
tatistically significantly reduced urinary cortisol excretion compared to the run-in period.
PULMICORT RESPULES (budesonide inhalation suspension) , like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods [see WARNINGS AND ]. Pharmacokinetics Absorption
In asthmatic children 4-6 years of age, the total absolute bioavailability (ie, lung + oral) following administration of PULMICORT RESPULES (budesonide inhalation suspension) via jet nebulizer was approximately 6% of the labeled dose.
In children, a peak plasma concentration of 2.6 nmol/L was obtained approximately 20 minutes after nebulization of a 1 mg dose. Systemic exposure, as measured by AUC and Cmax, is similar for young children and adults after inhalation of the same dose of PULMICORT RESPULES (budesonide inhalation suspension) . Distribution
In asthmatic children 4-6 years of age, the volume of distribution at steady-state of budesonide was 3 L/kg, approximately the same as in healthy adults. Budesonide is 85-90% bound to plasma proteins, the degree of binding being constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses. Budesonide showed little or no binding to corticosteroid-binding globulin. Budesonide rapidly equilibrated with in a concentration independent manner with a blood/plasma ratio of about 0.8. Metabolism
In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative difference between the and in vivo metabolic patterns has been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion/Elimination
Budesonide is primarily cleared by the liver. Budesonide is excreted in urine and feces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine.
In asthmatic children 4-6 years of age, the terminal half-life of budesonide after nebulization is 2.3 hours, and the systemic clearance is 0.5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight. Special Populations
No differences in pharmacokinetics due to race, gender, or age have been identified. Hepatic Insufficiency
Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy adults. Nursing Mothers
The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum . Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breast-feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels ( < 0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see Use In Specific Populations ]. Drug-Drug Interactions Inhibitors of cytochrome P450 enzymes
Ketoconazole : Ketoconazole, a strong inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide [see WARNINGS AND PRECAUTIONS and ].
Cimetidine : At recommended doses, , a nonspecific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide. Animal Toxicology Reproductive Toxicology
As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.4 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis) and at a subcutaneous dose of 500 mcg/kg in rats (approximately 4 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis). In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to 250 mcg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults on a mcg/m²
Three double-blind, placebo-controlled, parallel group, randomized U.S. clinical trials of 12-weeks duration each were conducted in 1018 pediatric patients, 6 months to 8 years of age, 657 males and 361 females (798 Caucasians, 140 Blacks, 56 Hispanics, 3 Asians, 21 Others) with persistent asthma of varying disease duration (2 to 107 months) and severity. Doses of 0.25 mg, 0.5 mg, and 1 mg administered either once or twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. A Pari-LC-Jet Plus Nebulizer (with a face mask or mouthpiece) connected to a Pari Master compressor was used to deliver PULMICORT RESPULES (budesonide inhalation suspension) to patients in the 3 U.S. controlled clinical trials . The co-primary endpoints were nighttime and daytime asthma symptom scores (0-3 scale). Improvements were addressed in terms of the primary efficacy variables of changes from baseline to the double-blind treatment period in nighttime and daytime asthma symptom scores (scale 0-3) as recorded in the patient diaries. Baseline was defined as the mean of the last seven days prior to randomization
Results of the 3
Improvements in lung function were associated with PULMICORT RESPULES (budesonide inhalation suspension) in the subgroup of patients capable of performing lung function testing. Statistically significant increases were seen in FEV 1
Patients Not Receiving Inhaled Corticosteroid Therapy
The efficacy of PULMICORT RESPULES (budesonide inhalation suspension) at doses of 0.25 mg, 0.5 mg, and 1 mg once daily was evaluated in 344 pediatric patients, 12 months to 8 years of age, with mild to moderate persistent asthma (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.07 to 1.34) who were not well controlled by bronchodilators alone. The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 1. Nighttime asthma symptom scores showed statistically significant decreases in the patients treated with PULMICORT RESPULES compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.
Changes from baseline to the double-blind phase for the budesonide treatment groups compared to placebo were made using analysis of variance techniques. The model included terms for the respective changes from baseline as the dependent variable and terms for treatment, center and treatment by center interaction as exploratory variables. (See Figures 1-3 ). Figure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline
Patients Previously Maintained on Inhaled Corticosteroids
The efficacy of PULMICORT RESPULES (budesonide inhalation suspension) at doses of 0.25 mg and 0.5 mg twice daily was evaluated in 133 pediatric asthma patients, 4 to 8 years of age, previously maintained on inhaled corticosteroids (mean FEV 1 79.5% predicted; mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.04 to 1.18; mean baseline dose of beclomethasone dipropionate of 265 mcg/day, ranging between 42 to 1008 mcg/day; mean baseline dose of triamcinolone acetonide of 572 mcg/day, ranging between 200 to 1200 mcg/day). The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 2. Nighttime asthma symptom scores showed statistically significant decreases in patients treated with PULMICORT RESPULES (budesonide inhalation suspension) compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.
Statistically significant increases in FEV 1 compared to placebo were observed with PULMICORT RESPULES (budesonide inhalation suspension) at a dose of 0.5 mg twice daily and in morning PEF for both doses (0.25 mg and 0.5 mg twice daily). Figure 2: A 12-Week Trial in Pediatric Patients Previously Maintained on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline
Patients Receiving Once-Daily or Twice-Daily Dosing
The efficacy of PULMICORT RESPULES (budesonide inhalation suspension) at doses of 0.25 mg once daily, 0.25 mg twice daily, 0.5 mg twice daily, and 1 mg once daily, was evaluated in 469 pediatric patients 12 months to 8 years of age (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.13 to 1.31). Approximately 70% were not previously receiving inhaled corticosteroids. The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 3. PULMICORT RESPULES at doses of 0.25 mg and 0.5 mg twice daily, and 1 mg once daily, demonstrated statistically significant decreases in nighttime asthma symptom scores compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.
PULMICORT RESPULES (budesonide inhalation suspension) at a dose of 0.5 mg twice daily resulted in statistically significant increases compared to placebo in FEV 1 , and at doses of 0.25 mg and 0.5 mg twice daily and 1 mg once daily statistically significant increases in morning PEF.
The evidence supports the efficacy of the same nominal dose of PULMICORT RESPULES (budesonide inhalation suspension) administered on either a once-daily or twice-daily schedule. However, when all measures are considered together, the evidence is stronger for twice-daily dosing (see DOSAGE AND ADMINISTRATION ). Figure 3: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline Medication Guide OVERDOSE
The potential for acute toxic effects following overdose of PULMICORT RESPULES (budesonide inhalation suspension) is low. If inhaled corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism or growth suppression may occur [see WARNINGS AND PRECAUTIONS , Hypercorticism and Adrenal Suppression
In mice, the minimal lethal inhalation dose was 100 mg/kg (approximately 410 and 120 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In rats there were no deaths at an inhalation dose of 68 mg/kg (approximately 550 and 160 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In mice, the minimal oral lethal dose was 200 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In rats, the minimal oral lethal dose was less than 100 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults or and children 12 months to 8 years of age on a mg/m² Hypersensitivity to budesonide or any of the ingredients of PULMICORT RESPULES [see WARNINGS AND PRECAUTIONS , DESCRIPTION and ADVERSE REACTIONS , Post-marketing Experience

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k1002 said…
iPoop, partlycloudy:
The GI at the hospital decided that I should start Inflectra after a failed transition from IV steroids to Prednisone which caused me to faint after 2 days of bloody BMs. My first dose was at what I believe is the normal dosage at 5mg/kg. One week later, I was still having bloody mucus so the GI told me that they are going to be more aggressive and give me another dose at 10mg/kg (one week after the first one). Two weeks after my second dose, I got a third dose at 5mg/kg. My fourth dose four weeks later, and fifth six weeks after that (both at 5mg/kg).
I was symptom free half a week after my second dose (aside from some pain during BMs for the first week) and remained symptom free for four weeks while tapering Prednisone. Then I started seeing a bit of blood just before my fourth dose and halfway through my course of Prednisone, then things started going downhill again. Long story short, I ended up in the hospital again (two months and a half since I got discharged), that’s when the GI decided to push my fifth dose forward by two weeks, try to max out inflectra/check levels, and check to see if I can take Aza with inflectra.
No results on any of the blood tests yet. I do have an appointment with my GI before my next dose of inflectra (8 weeks after the fifth dose) and hopefully I’ll get some answers then because I haven’t been so lucky this time (got discharged from the hospital okay, got my fifth dose the next day, got a bit of bloody mucus with my once per day normal BM that progressed into bloody (not horribly) BMs roughly 3 times a day, and I’ve just begun my Prednisone taper).
Personally I’d drop inflectra if it’s not doing anything (less meds to be on and save money) rather than be on both inflectra and Aza. My GI also said that I shouldn’t be on so many immune suppressors at a time (Prednisone, inflectra, Aza) anyway. And if TNF-alpha is not the thing causing my UC, then inflectra really isn’t helping.
Have you had stool tests done to rule out superimposed infections?
Are you still on prednisone? If so, what dose?

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Takeda Receives Positive CHMP Opinion for ADCETRIS® (brentuximab vedotin) for the Treatment of Adult Patients with Previously Untreated CD30+ Stage IV Hodgkin Lymphoma in Combination with AVD

<h1>Takeda Receives Positive CHMP Opinion for ADCETRIS® (brentuximab vedotin) for the Treatment of Adult Patients with Previously Untreated CD30+ Stage IV Hodgkin Lymphoma in Combination with AVD</h1>

Takeda Receives Positive CHMP Opinion for ADCETRIS® (brentuximab vedotin) for the Treatment of Adult Patients with Previously Untreated CD30+ Stage IV Hodgkin Lymphoma in Combination with AVD

CAMBRIDGE, Mass. & OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for the extension o…

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Leukemia Lymphoma Myelodysplastic Syndromes (MDS) Myeloma Myeloproliferative Neoplasms (MPNs)

<h1>Leukemia Lymphoma Myelodysplastic Syndromes (MDS) Myeloma Myeloproliferative Neoplasms (MPNs)</h1>

Leukemia Lymphoma Myelodysplastic Syndromes (MDS) Myeloma Myeloproliferative Neoplasms (MPNs)

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After ASCT, it is know… http://www.bloodjournal.org/content/132/Suppl_1/5905 Nov 21st, 2018 – Aims: The objective of this study was to compare the efficacy and safety of pegfilgrastim in patients affected by heavily pretreated MM, treated with pomalidomide-dexamethasone, in order to determine whether a single subcutaneous injection of pegfilgrastim is as effective as daily injections of standard filgrastim, in terms of haematological toxicity, febrile neutropenic episodes, antibiotic us… http://www.bloodjournal.org/content/132/Suppl_1/5268 Nov 21st, 2018 – Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous disorder. Precision therapies for AML have been developed that target specific driver mutations. The efficacies of these therapies are variable, making it critical to determine successful therapies prior to patient relapse. For patients achieving a first complete remission, minimum residual disease (MRD) is an import… http://www.bloodjournal.org/content/132/Suppl_1/5914 Nov 21st, 2018 – Introduction. Cancer-related cognitive impairment is a distressing symptom that affects numerous patients after cancer therapy, including those treated for hematological malignancy. The lack of effective interventions has driven interest in determining underlying mechanisms. Accumulating evidence in the context of solid tumours suggests inflammatory processes are involved in the development of … http://www.bloodjournal.org/content/132/Suppl_1/5903 Nov 21st, 2018 – Objective: To investigate the clinical features of 2nd hematological malignancies post to the initial cancer treatment. METHODS: A retrospective study was performed to analyze the available clinical data of 116 patients diagnosed with 2nd hematologic malignancies after treatment of various malignant tumors from June 1998 to June 2018 at Sun Yat-sen University cancer center. RESULTS: The charact… http://www.bloodjournal.org/content/132/Suppl_1/4098 Nov 21st, 2018 – Background: Resistance to apoptosis is one of the hallmarks in hematological neoplasms, most typically via dysregulation of the intrinsic mitochondrial pathway. The most important antiapoptotic/pro-survival proteins in this pathway are BCL2, BCL2L1 and MCL1. Molecules targeting each of these proteins are in various stages of preclinical and clinical development. The BCL2 inhibitor venetoclax is… http://www.bloodjournal.org/content/132/Suppl_1/1610 Nov 21st, 2018 – Introduction: As in multiple myeloma, Waldenström macroglobulinemia (WM) is preceded by an asymptomatic phase, mainly as monoclonal gammopathy of undetermined significance (MGUS) or by a smoldering WM (SWM) phase. It has recently been reported that patients with IgM MGUS have a higher risk of progression in comparison to those with other MGUS isotypes. Moreover, it has been described that if th… http://www.bloodjournal.org/content/132/Suppl_1/4178 Nov 21st, 2018 – While monoclonal antibodies (MoAb) are already well established for the treatment of B cell-derived malignancies and usually show a good safety profile, not all patients benefit and relapses may be a problem. In order to identify novel surface structures suitable for antibody-based therapies and to improve killing mechanisms, 'EBU-141 Tetra' was developed. The parental MoAb EBU-141 is of mouse … http://www.bloodjournal.org/content/132/Suppl_1/5320 Nov 21st, 2018 – Background: We recently reported that the International Prognostic Scoring System for Waldenström macroglobulinemia (ISSWM), which is widely used to predict the prognosis of WM patients, might not be applicable to Japanese patients, and evidence of pleural effusion might be a novel adverse prognostic factor for symptomatic WM in the rituximab era. Further studies with a large number of patients… http://www.bloodjournal.org/content/132/Suppl_1/4604 Nov 21st, 2018 – BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is now standard of care for newly diagnosed patients with multiple myeloma (MM) and is used for some forms of non-Hodgkin lymphoma, providing improved outcomes. ASCT has been associated with a high incidence of engraftment syndrome (ES), which clinically presents as skin rashes, diarrhea, non-infectious f… http://www.bloodjournal.org/content/132/Suppl_1/5383 Nov 21st, 2018 – Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes…. http://www.bloodjournal.org/content/132/Suppl_1/5300 Nov 21st, 2018 – Primary effusion lymphoma (PEL) is a rare, aggressive form of B-cell lymphoma. With a median survival time of around six months the prognosis for PEL patients is poor. Therefore, there is a medical need for novel therapeutic strategies. We performed expression array analysis to find potential targets for antibody-based therapy. Unsupervised clustering analysis revealed that PEL cell lines group… http://www.bloodjournal.org/content/132/Suppl_1/4382 Nov 21st, 2018 – Introduction Myelodysplastic syndromes (MDS) are heterogeneous myeloid disorders characterized by dysplasia in one or more hematopoietic cell lines, peripheral cytopenia(s), and distinct cytogenetic abnormalities. The presence of certain cytogenetic abnormalities [e.g. 7/del(7q), -5/del(5q), 13/del(13q), i(17p)], in the setting of unexplained persistent cytopenia, has been considered presumptiv… http://www.bloodjournal.org/content/132/Suppl_1/1908 Nov 21st, 2018 – A proliferation-inducing ligand (APRIL) is produced by multiple accessory and myeloid cells in the bone marrow niche. Through binding to its receptors B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI), APRIL plays an important role in the development and maintenance of cells derived from the B cell lineage. Both APRIL and its receptors have been identified … http://www.bloodjournal.org/content/132/Suppl_1/3039 Nov 21st, 2018 – Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) that can progress to post-PV (PPV) myelofibrosis (MF) and post-ET (PET) MF, from now on referred to as secondary myelofibrosis (SMF). Recent studies have shown an increased risk of developing solid tumors (ST) in MPN patients in comparison to the general population. Information on develo… http://www.bloodjournal.org/content/132/Suppl_1/4483 Nov 21st, 2018 – Purpose : This study evaluated the prognostic role of 18F-FDG PET/CT at baseline in patients with newly diagnosed multiple myeloa (MM) and evaluated the prognostic relevance of 18F-FDG PET/CT for each stage according to the Revised International Staging System (R-ISS). Method: We retrospectively analyzed the records of 167 patients with newly diagnosed MM. 18F-FDG PET/CT was performed prior to … http://www.bloodjournal.org/content/132/Suppl_1/1975 Nov 21st, 2018 – Introduction: The median progression free survival (PFS) and overall survival (OS) of multiple myeloma (MM) patients have been prolonged due to novel agents combined with ASCT but the median OS in MM is still 7-8 years. Thus, the feasibility of new combinations and dosing of available agents must be investigated. The first proteasome inhibitor (PI), bortezomib (B), combined with elotuzumab and … http://www.bloodjournal.org/content/132/Suppl_1/3254 Nov 21st, 2018 – Introduction: In the ASPIRE and ENDEAVOR trials, multiple myeloma (MM) patients treated with carfilzomib (K) had significantly improved progression‐free survival and overall survival compared with standard of care. The incidence of all-grade adverse cardiovascular events (ACVE) was 26.6% and 24.5% in the K treated groups in ASPIRE and ENDEAVOR respectively. The atherosclerotic cardiovascular di… http://www.bloodjournal.org/content/132/Suppl_1/1981 Nov 21st, 2018 – Introduction: Patients (pts) with newly diagnosed multiple myeloma (MM) are commonly treated with the standard of care combination of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex), also known as RVD. A recent randomized phase 3 study found that the addition of Bz to Len and Dex significantly increased median overall and progression free survival as well as response rate (Durie et… http://www.bloodjournal.org/content/132/Suppl_1/3203 Nov 21st, 2018 – Background: The oncogenic drivers and progression factors in multiple myeloma (MM) are heterogeneous and difficult to target therapeutically. As a result, personalized medicine approaches have not yet been realized. However, clinical availability of numerous anti-myeloma drugs and readily obtainable bone marrow (BM) aspirates raises the possibility to benefit patients by profiling the drug sens… http://www.bloodjournal.org/content/132/Suppl_1/1008 Nov 21st, 2018 – Multiple myeloma is the second most common hematological malignancy in the U.S. with an estimated 30,700 new diagnoses in 2018. It is a clonal disease of plasma cells that, despite recent therapeutic advances, remains incurable. Myeloma cells retain numerous characteristics of normal plasma cells including reliance on survival signals in the bone marrow for long term viability. However, maligna… http://www.bloodjournal.org/content/132/Suppl_1/56 Nov 21st, 2018 – Introduction: Multiple Myeloma (MM) is consistently preceded by pre-malignant asymptomatic monoclonal gammopathies (AMG). To date, our understanding of the pathogenesis of progression to MM remains incomplete. Genetic analyses of AMG cells compared to MM-derived plasma cells (PCs) have found few differences, suggesting that progression may be mediated in part by tumour-extrinsic mechanisms. To … http://www.bloodjournal.org/content/132/Suppl_1/799 Nov 21st, 2018 – Introduction: Triplet regimens incorporating a proteasome inhibitor and immunomodulatory drug are standards of care for the treatment of patients with newly diagnosed multiple myeloma (NDMM). The combinations of carfilzomib-lenalidomide-dexamethasone (KRd) and bortezomib-lenalidomide-dexamethasone (VRd) are recommended regimens for the treatment of NDMM by the National Comprehensive Care Networ… http://www.bloodjournal.org/content/132/Suppl_1/3308 Nov 21st, 2018 – Introduction The first two trials to test the activity of daratumumab (DARA) in relapsed/refractory multiple myeloma (MM) were GEN501 (DARA monotherapy) and GEN503 (DARA in combination with lenalidomide [LEN] and dexamethasone [DEX]). GEN501 enrolled 104 participants from 2008 and GEN503 enrolled 45 participants from 2012. GEN501 has been completed; GEN503 is active but has finished accrual. We… http://www.bloodjournal.org/content/132/Suppl_1/406 Nov 21st, 2018 – Introduction: Multiple myeloma, a malignant proliferation of differentiated plasma cells, is the second most commonly diagnosed hematologic malignancy, and the number of cases may grow by almost 60% between 2010 and 2030. Recent therapeutic advances, including the use of proteasome inhibitors (PIs), have contributed to a doubling of the median overall survival in myeloma patients. This has been… http://www.bloodjournal.org/content/132/Suppl_1/110 Nov 21st, 2018 – Introduction: The study of multiple myeloma (MM) genomics has identified many abnormalities that are associated with poor progression free survival (PFS) and overall survival (OS). Copy number abnormalities have been extensively studied in many datasets with long follow-up, however, the prognostic impact of mutations have not been extensively studied and available datasets have generally had a … http://www.bloodjournal.org/content/132/Suppl_1/473 Nov 21st, 2018 – Background Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide-dexamethasone (Rd) for pts with MM who have received at least 1 prior therapy. Approval was based on the phase 3 TOURMALINE-MM1 study (NCT01564537), in which ixazomib showed a consistent progression-free survival (PFS) benefit in combination with Rd (IRd) in the ITT population as well as in pr… http://www.bloodjournal.org/content/132/Suppl_1/1912 Nov 21st, 2018 – Background The survival of patients with multiple myeloma (MM) has improved significantly over the past two decades with the introduction of novel treatment agents. However, MM is still largely considered an incurable malignancy with a relapsing-remitting course. A follow-up of at least 10 years from active disease is required to determine whether a plateau in progression-free survival has been… http://www.bloodjournal.org/content/132/Suppl_1/3261 Nov 21st, 2018 – Chimeric Antigen Receptors (CARs) are engineered transmembrane proteins consisting of an antibody-derived antigen recognition domain linked to intracellular cell signaling domains. CAR engineered autologous T cells have been successful in the treatment of a variety of hematologic malignancies. However, several major caveats, including lack of universal donors, long manufacturing times, and abse… http://www.bloodjournal.org/content/132/Suppl_1/187 Nov 21st, 2018 – INTRODUCTION. Systemic light chain amyloidosis (AL) is caused by accumulation of plasma cells producing misfolded monoclonal light chains depositing as amyloid fibrils in different organs, most frequently heart and kidney. AIM of our study is first assessing the molecular characteristics of malignant plasma cells from AL-patients in relation to those from MGUS, asymptomatic, and symptomatic mye… http://www.bloodjournal.org/content/132/Suppl_1/3224 Nov 21st, 2018 – Daratumumab targets the cell surface protein CD38 and is the only FDA approved monoclonal antibody that has demonstrated single agent efficacy in relapsed refractory myeloma. CD38 is broadly expressed in the immune system, and its high expression on multiple myeloma cells allows for effective targeting by daratumumab. Daratumumab induces myeloma cell death through multiple mechanisms, including… http://www.bloodjournal.org/content/132/Suppl_1/2024 Nov 21st, 2018 – Introduction: Multiple Myeloma (MM) is a hematologic cancer caused by malignant plasma cells. Daratumumab is an immunoglobin G1 kappa human monoclonal antibody that targets CD38 antigen which is a cell surface glycoprotein highly expressed on myeloma cells. Daratumumab is FDA approved as monotherapy and in combination with dexamethasone and lenalidomide, bortezomib or pomalidomide in relapsed/r… http://www.bloodjournal.org/content/132/Suppl_1/152 Nov 21st, 2018 – Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed (ND) MM. CyBorD is another commonly used immunomodulatory drug-sparing regimen for MM. We evaluated the safety and efficacy of dara-CyBorD and administered the first dara infusion as a split dose over 2 days in pts… http://www.bloodjournal.org/content/132/Suppl_1/1942 Nov 21st, 2018 – Multiple myeloma (MM) is an incurable cancer of plasma cells (PC), with a median survival of 5-7 years. Osteolytic bone disease and skeletal complications occur in more than 80% of MM patients and significantly contribute to the morbidity and mortality of these patients. Glycosphingolipid (GSL), an essential constituent of the outer leaflet of the cellular membrane, is altered in MM and other h… http://www.bloodjournal.org/content/132/Suppl_1/4477 Nov 21st, 2018 – Background:In 2015, the International Myeloma Working Group (IMWG) developed the Revised International Staging System (R-ISS), which combined the ISS with the status of high-risk cytogenetic abnormalities (CAs) and serum levels of lactate dehydrogenase to identify three multiple myeloma (MM) entities with clearly different outcomes. However, although MM tends to affect older adults, the origina… http://www.bloodjournal.org/content/132/Suppl_1/4489 Nov 21st, 2018 – Introduction Chromosome instability (CIN) is a driver of copy number aberrations (CNAs) in cancer, and is a major factor leading to tumor heterogeneity and resistance to therapy. By definition, CIN is an increased rate or ongoing acquisition and accumulation of CNAs and not simply the existence of structurally and numerically abnormal aneuploid clones. In multiple myeloma (MM), the most common … http://www.bloodjournal.org/content/132/Suppl_1/802 Nov 21st, 2018 – Background The benefit of single agent maintenance is largely established from studies in newly diagnosed patients, while extended therapy combination regimens are more commonly used in relapsed disease. Extended therapy on combination protocols may be limited by tolerability and safety, as well as patient compliance. Fixed duration combination treatment followed by single agent maintenance may… http://www.bloodjournal.org/content/132/Suppl_1/58 Nov 21st, 2018 – Background Loss of immune surveillance is thought to contribute to disease progression and treatment resistance in a range of malignancies including multiple myeloma (MM). Understanding the degree and pattern of immunological abnormality present within the bone marrow microenvironment at the time of MM diagnosis is vital if we are to utilize emerging immunological therapeutic strategies success… http://www.bloodjournal.org/content/132/Suppl_1/3173 Nov 21st, 2018 – The B-cell maturation antigen (BCMA) is selectively expressed by cells of the B-lineage, including multiple myeloma (MM) cells, and constitutes a promising target for immunotherapeutic approaches. At present, BCMA is being evaluated as target for immunotherapeutic approaches, such as CAR T cells and bispecific antibodies, which have demonstrated promising results in phase I clinical trials. The… http://www.bloodjournal.org/content/132/Suppl_1/3209 Nov 21st, 2018 – A proliferation inducing ligand (APRIL) is a natural ligand with higher affinity than BAFF for both B cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI), which are overexpressed on multiple myeloma (MM) cells. APRIL, which is abundantly secreted by myeloma-supporting osteoclasts and macrophages, promotes MM cell progression in vivo and further induces regulato… http://www.bloodjournal.org/content/132/Suppl_1/3280 Nov 21st, 2018 – Background: The depth of response both pre- and post- autologous stem cell transplant (ASCT) has been shown to correlate with clinical outcome for myeloma patients. Maximizing response can be achieved by modifying therapy either at induction, transplant, consolidation or during maintenance. In this work we explore the role of pre-transplant induction therapy in the UK NCRI Myeloma XI clinical t… http://www.bloodjournal.org/content/132/Suppl_1/1916 Nov 21st, 2018 – Introduction: Despite recent advances in treatment, multiple myeloma (MM) is still considered incurable. Several novel therapies with different mechanisms of action are currently being studied for use in MM. These include targeted therapies such as pathway inhibitors and BCL-2 homology domain 3 (BH3) mimetics. BH3-mimetics overcome apoptosis resistance by binding and inhibiting select pro-survi… http://www.bloodjournal.org/content/132/Suppl_1/1984 Nov 21st, 2018 – Background: Carfilzomib, a second generation proteosome inhibitor, is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Recent phase II and phase III trials have demonstrated the efficacy of weekly dosing strategies. The aim of this study was to examine high dose once weekly carfilzomib in combination with weekly dexamethasone and low dose weekly cyclophosphamide (w… http://www.bloodjournal.org/content/132/Suppl_1/3287 Nov 21st, 2018 – Background: Multiple myeloma (MM) is a disease of older adults with a median age of onset of 70 years. Approximately 20% of the incident cases are diagnosed in patients 85 years and older. There is significant heterogeneity among older adults with regards to the tolerability of myeloma directed therapy. In newly diagnosed transplant ineligible patients with MM, available evidence indicates that… http://www.bloodjournal.org/content/132/Suppl_1/1882 Nov 21st, 2018 – Introduction The multiple myeloma (MM) tumor microenvironment (TME) strongly influences patient outcomes as evidenced by the success of immunomodulatory therapies. To develop precision immunotherapeutic approaches, it is essential to identify and enumerate TME cell types and understand their dynamics. Methods We estimated the population of immune and other non-tumor cell types during the course… http://www.bloodjournal.org/content/132/Suppl_1/959 Nov 21st, 2018 – Introduction: BCMA targeted CAR T cell therapy has shown promising results in patients with relapsed/refractory multiple myeloma (MM). Herein, we report on the safety and efficacy of MCARH171, a second generation, human derived BCMA targeted autologous 4-1BB containing CAR T cell therapy, including a truncated epidermal growth factor receptor safety system (Smith EL. Mol Ther 2018). Methods: Th… http://www.bloodjournal.org/content/132/Suppl_1/1891 Nov 21st, 2018 – Introduction: Drivers that underlie the progression of MGUS (Monoclonal gammopathy of undetermined significance) to multiple myeloma are yet largely unknown. Because of the vast number of potential players, these drivers may not necessarily aimed to transform plasma cell or the bone marrow niche, but rather remodel a supporting microenvironment. Metabolic alterations have been linked to cancer … http://www.bloodjournal.org/content/132/Suppl_1/1011 Nov 21st, 2018 – Background: Despite advances in the treatment of multiple myeloma (MM) almost all patients relapse and high risk features continue to portend a short median survival. The adoptive transfer of B-Cell Maturation Antigen (BCMA) chimeric antigen receptor (CAR) T cells is demonstrating early promise in MM, but the durability of response has not been established. The infusion of genetically modified … http://www.bloodjournal.org/content/132/Suppl_1/3223 Nov 21st, 2018 – Background: Histone deacetylases (HDACs) are potential novel therapeutic targets for multiple myeloma (MM) treatment. A pan-HDAC inhibitor (HDI) panobinostat was approved by the FDA in 2015 to treat relapsed/refractory MM patients, and several other HDIs are currently in different phases of clinical trials. However, unfavorable side-effects of the non-selective HDIs necessitate further dissecti… http://www.bloodjournal.org/content/132/Suppl_1/3222 Nov 21st, 2018 – Introduction: MM is characterized by the accumulation of aberrant BM plasma cells (aPCs). The use of novel agents for anti-MM treatment has enabled the achievement of deeper responses and prolonged progression free survival (PFS) and overall survival (OS). These advances have created the need for sensitive means to detect residual PCs. MFC allows aPC detection with high sensitivity and is used … http://www.bloodjournal.org/content/132/Suppl_1/1968 Nov 21st, 2018 – Advances in the management of multiple myeloma (MM) led to a significant prolongation of overall survival (OS), mainly of the younger patients; almost 10% of them experience more than 10-year OS. Although long progression-free survival (PFS) correlates with extended OS, there is very limited information for the characteristics of patients who manage to be progression-free for a long period afte… http://www.bloodjournal.org/content/132/Suppl_1/4461 Nov 21st, 2018 – INTRODUCTION: Progression from precursor states, MGUS and smoldering multiple myeloma (SMM), to multiple myeloma (MM) is dependent upon adaptive and innate immune contexture shaped by cross-talk between malignant plasma cells and bone marrow (BM) milieu. The complexity and heterogeneity of interactions between the immune system and plasma cells in BM triggers alterations in peripheral blood (PB… http://www.bloodjournal.org/content/132/Suppl_1/3210 Nov 21st, 2018 – Introduction Regardless of significant advances in the therapy of multiple myeloma (MM) there is still a lack of effective treatment options for patients with high-risk disease. In this context, we recently developed a network of high-risk disease based on more than 30 000 genomic and clinical variables from 645 patients of the CoMMpass dataset (Gruber et al., ASH 2016). Validation of these fin… http://www.bloodjournal.org/content/132/Suppl_1/4496 Nov 21st, 2018 – Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a prevalent hematological condition among elderly population with incidence rates of 3% and 5% over the age of 50 and 70 years, respectively (Kyle et al., 2018). It is considered a premalignant state of multiple myeloma with a risk of progression of 1% per year. It has also been shown that MGUS patients have a shorter sur… http://www.bloodjournal.org/content/132/Suppl_1/1898 Nov 21st, 2018 – Introduction: Gene fusions are the result of genomic rearrangements that create hybrid protein products or bring the regulatory elements of one gene into close proximity of another. Fusions often dysregulate gene function or expression through oncogene overexpression or tumor suppressor underexpression (Gao, Liang, Foltz, et al. Cell Rep 2018). Some fusions such as EML4–ALK in lung adenocarcin… http://www.bloodjournal.org/content/132/Suppl_1/4458 Nov 21st, 2018 – Monoclonal gammopathies, including multiple myeloma (MM), represent a group of plasma cell (PC) disorders that comprise of mostly incurable hematopoietic malignancies with an increasing incidence in the US. Previous epidemiological studies demonstrated a 2-3 fold higher incidence of monoclonal gammopathy of undetermined significance (MGUS) and a similarly higher incidence of MM along with a ~4-… http://www.bloodjournal.org/content/132/Suppl_1/3279 Nov 21st, 2018 – Background Data from the Australian and New Zealand (ANZ) Myeloma and Related Diseases Registry (MRDR) shows that 85% of newly diagnosed multiple myeloma (NDMM) patients (pts) in ANZ are induced with bortezomib(V)-containing therapies, predominantly triplets of V-cyclophosphamide-dexamethasone (VCD). Of these, 15% demonstrate treatment failure – either a sub-optimal response ( http://www.bloodjournal.org/content/132/Suppl_1/3197 Nov 21st, 2018 – CRISPR/Cas9-based gene editing has become a powerful tool for loss-of-function (LOF) studies and has allowed us to systematically interrogate the function of genes regulating the survival and proliferation of multiple myeloma (MM) cells in vitro, in vivo and in the context of treatment resistance (e.g. De Matos Simoes et al., Shirasaki et al., and Gandolfi et al. ASH 2017). We reasoned, however… http://www.bloodjournal.org/content/132/Suppl_1/595 Nov 21st, 2018 – Background: Isatuximab (ISA) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells via direct tumor targeting and immune cell engagement. ISA, combined with bortezomib, has demonstrated strong potentiation in a multiple myeloma (MM) xenograft model (Clin Cancer Res 2014:20:4754). This supported evaluation of ISA with bortezomib combinations in pts with newly … http://www.bloodjournal.org/content/132/Suppl_1/3170 Nov 21st, 2018 – Background: Since survival in AL mainly depends on the extent of organ involvement of patients at presentation, early diagnosis and risk stratification are key to improve patients' outcome. Therefore, together with surrogates of organ involvement, biomarkers identifying patients with MGUS or MM at greater risk of developing AL would be highly valuable to prevent organ damage, to maximize therap… http://www.bloodjournal.org/content/132/Suppl_1/1907 Nov 21st, 2018 – Introduction Multiple myeloma (MM) is a plasma cell malignancy that manifests continuous cell dissemination to multiple bone marrow (BM) niches and extramedullary (EM) sites. However, the molecular mechanisms behind this phenomenon remain elusive. CD45, a receptor tyrosine phosphatase, is an important regulator for T-cell and B-cell signaling pathways. In MM, the loss of CD45 expression has bee… http://www.bloodjournal.org/content/132/Suppl_1/3904 Nov 21st, 2018 – Introduction: Multiple myeloma (MM) is characterized by the over-expression of D-cyclin genes and the expression is tightly linked to cytogenetic subgroups. For instance, overexpression of CCND1 in the t(11;14) and CCND3 in the t(6;14) is direct through IgH super-enhancer translocation, and CCND2 overexpression in t(4;14), t(14;16) and t(14;20) indirectly, presumably as a result of transcriptio… http://www.bloodjournal.org/content/132/Suppl_1/4462 Nov 21st, 2018 – The APOBEC family of cytidine deaminases include AID (activity induced deaminase) and 10 related APOBEC enzymes (A1,A2,A3A,A3B,A3C,A3D,A3F,A3G,A3H and A4). AID is well studied for its role in somatic hyper mutation and class switch recombination of immunoglobulin genes. APOBECs (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) have been shown to have roles in mRNA editing and i… http://www.bloodjournal.org/content/132/Suppl_1/4486 Nov 21st, 2018 – Seventy percent of all patients with light chain amyloidosis (AL) have cardiac involvement, and most of those patients ultimately die from complications related to their heart disease. While consensus guidelines outline criteria for grading hematologic response to chemotherapy for AL, there are no currently validated criteria for grading cardiac response to therapy. Recently, Muchtar et al. cre… http://www.bloodjournal.org/content/132/Suppl_1/3242 Nov 21st, 2018 – Introduction: Daratumumab (DARA), a human IgG1k monoclonal antibody with single activity in multiple myeloma (MM) shows strong synergy in combination with other anti-MM agents, including immunomodulatory drug (IMiDs) and proteasome inhibitors (PI). This has led to the exploration of DARA in combination with front line regimens. Triplets including a PI and an IMiD are considered an ideal backbon… http://www.bloodjournal.org/content/132/Suppl_1/593 Nov 21st, 2018 – Background: Deletion (del) of 17p involving the p53 tumor suppressor (TP53) remains an adverse prognostic factor in multiple myeloma (MM) despite the use of novel agents as well as high-dose chemotherapy with autologous stem cell rescue. Genomic TP53 deletion can cause haploinsufficiency of nearby genes, such as RNA polymerase II subunit A (POLR2A), which ia also located on 17p13.1. We therefor… http://www.bloodjournal.org/content/132/Suppl_1/3274 Nov 21st, 2018 – Background and aims Treatment of relapsed/refractory myeloma (RRMM) remains a challenge as most approved and commonly accessible doublet treatments induce responses (≥PR) in less than half of patients. The combination of the classical alkylator cyclophosphamide with thalidomide (CTD) or lenalidomide (CRD) is standard of care in early lines of therapy in the UK and elsewhere. Data on the clinica… http://www.bloodjournal.org/content/132/Suppl_1/951 Nov 21st, 2018 – Multiple myeloma is a malignancy of long-lived plasma cells of the bone marrow that is rarely curable. Thus, despite recent advances in the development of new therapies, additional approaches are required. We investigated potential molecular vulnerabilities in the BCL2 family. Using the MMRF CoMMpass (NCT0145429) study (IA13), we determined the frequency of nonsynonymous coding mutations in the… http://www.bloodjournal.org/content/132/Suppl_1/2004 Nov 21st, 2018 – Background: Hematogenous extramedullary multiple myeloma (HEMM), though rare, is mainly observed in MM patients at relapse. The current study assesses the characteristics and outcomes of patients with MM who develop HEMM in the novel agent era. Methods: Consecutive patients, treated in 16 participating centers and diagnosed with HEMM, were included. Patient characteristics at diagnosis and at H… http://www.bloodjournal.org/content/132/Suppl_1/55 Nov 21st, 2018 – Introduction: Multiple Myeloma (MM) is a genetically complex and evolutionary process with well defined precursor states, which offer a unique opportunity to study the sequential evolution of the disease. A small number of detectable pre-malignant clones are present in early stage and continue to acquire more genomic abnormalities leading to overt disease. The interaction between cancer cells a… http://www.bloodjournal.org/content/132/Suppl_1/122 Nov 21st, 2018 – Introduction Multi-agent induction chemotherapy followed by autologous stem cell transplant (ASCT) is a standard of care for younger patients with multiple myeloma, aimed at maximising the depth and duration of first response (PFS1). However, the duration of PFS1 is variable between patients. Improved understanding of how to identify high risk patients who relapse early and the ability to desig… http://www.bloodjournal.org/content/132/Suppl_1/3897 Nov 21st, 2018 – Introduction: Poor prognosis and drug resistance in multiple myeloma (MM) is associated with increased mutational load. APOBEC3B is a major contributor to mutagenesis, especially in myeloma patients with t(14;16) MAF subgroup. It was shown recently that presence of the APOBEC signature at diagnosis is an independent prognostic factor for progression free survival (PFS) and overall survival (OS)… http://www.bloodjournal.org/content/132/Suppl_1/243 Nov 21st, 2018 – Introduction The multistep progression of multiple myeloma from a normal plasma cell to a system with the features of invasive cancer provides a unique opportunity to understand the co-evolution of the malignant clone within its microenvironment. Understanding these changes is becoming increasingly important as we attempt to design early intervention strategies and to precisely leverage emergin… http://www.bloodjournal.org/content/132/Suppl_1/1929 Nov 21st, 2018 – Introduction: Multiple myeloma (MM) cells from patients with smoldering MM (SMM) and low-risk (LR) MM harbor genetic alterations typically seen in patients with high-risk (HR) disease. To test whether the bone marrow (BM) microenvironment plays a role in controlling growth of LR MM cells, we established an experimental model that mimics a HR microenvironment by co-culturing normal mesenchymal s… http://www.bloodjournal.org/content/132/Suppl_1/4475 Nov 21st, 2018 – Introduction After therapy or stem cell transplantation, multiple myeloma patients achieving complete response (CR) or stringent complete response (sCR) can still have a significant risk of disease relapse, illustrating the importance of using highly sensitive methods for minimal residual disease (MRD) detection and prognostication. Two techniques used clinically for MRD detection include multi… http://www.bloodjournal.org/content/132/Suppl_1/1976 Nov 21st, 2018 – Chimeric antigen receptor T cells (CART) targeting CD19 have shown substantial activity against leukemia and lymphoma, which motivated developing CART cell therapy for Multiple myeloma (MM). B cell maturation antigen (BCMA) is the target molecule in MM. Several kinds of CART targeting BCMA have been created from 2016. Among these, the Bluebird Bio uses the humanized murine BCMA scFv to make CAR… http://www.bloodjournal.org/content/132/Suppl_1/4459 Nov 21st, 2018 – Background: A renewed interest in immune and cellular based therapeutics in multiple myeloma was recently fueled by the development of CD38 targeting monoclonal antibodies as well as the introduction of engineered CAR-T cells. Daratumumab treatment in myeloma patients was demonstrated to expand clonal CD8+T cells and T cell clonality was correlated with the depth of response consistent with a d… http://www.bloodjournal.org/content/132/Suppl_1/1945 Nov 21st, 2018 – Background: Multiple myeloma (MM) requires combination drug therapies to delay acquired drug resistance and clinical relapse. We co-developed CX-5461, a highly-selective inhibitor of RNA polymerase I-mediated rDNA transcription(1), currently in phase I trials for relapsed haematological malignancies (Peter Mac). CX-5461 produces a targeted nucleolar DNA damage response (DDR), triggering both a … http://www.bloodjournal.org/content/132/Suppl_1/403 Nov 21st, 2018 – Background Survival in multiple myeloma ranges from months to decades and the majority of patients remain incurable with current treatment approaches. Given this high variability, it would be clinically very useful to quantitatively predict survival on a continuous scale. Current risk prediction models attribute patients to 2-3 groups, i.e. high, intermediate, and low risk. Group size and survi… http://www.bloodjournal.org/content/132/Suppl_1/3201 Nov 21st, 2018 – Introduction: Daratumumab (Dara) is a human monoclonal antibody targeting the highly expressed multiple myeloma (MM) surface receptor CD38, with significant activity in relapsed MM. However, resistance to Dara develops in virtually all patients (pts). Thus, in order to maximize its clinical activity and prevent resistance, it is imperative to understand why pts stop responding. Our group recent… http://www.bloodjournal.org/content/132/Suppl_1/3255 Nov 21st, 2018 – Background: Carfilzomib (CFZ) is a potent, irreversible proteasome inhibitor (PI) licenced in patients with multiple myeloma (MM) demonstrating improved progression free and overall survival (OS) to standard of care therapies. However, CFZ is also associated with hypertension (HTN) and rarely cardiac toxicity. The exact mechanism is unclear but may be due to a disturbance of endothelial nitric … http://www.bloodjournal.org/content/132/Suppl_1/3257 Nov 21st, 2018 – Background: Daratumumab is one of the most effective new myeloma drugs recently approved for relapsed/refractory multiple myeloma (MM), first in monotherapy in heavily pretreated patients, later in triplet combinations from first relapse, based on the results of the SIRIUS, POLLUX and CASTOR trials that showed good tolerability and high effectivity of daratumumab both in monotherapy and combine… http://www.bloodjournal.org/content/132/Suppl_1/956 Nov 21st, 2018 – Background: Promising results are seen from several early phase clinical trials on the cellular immunotherapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) targeting B cell maturation antigen (BCMA) for the treatment of relapsed/refractory (RR) multiple myeloma (MM). We developed an anti-BCMA CAR-T cell product manufactured via gamma-retrovirus-mediated transduction of activated… http://www.bloodjournal.org/content/132/Suppl_1/405 Nov 21st, 2018 – Patients with the plasma cell malignancy multiple myeloma now benefit from treatments such as proteasome inhibitors, immunomodulatory imide drugs (IMiDs), autologous stem cell transplant, and monoclonal antibodies. However, 20% of patients still relapse or die within two years and are deemed 'high risk'. Current markers fail to identify all high-risk patients resulting in misdiagnoses, therefor… http://www.bloodjournal.org/content/132/Suppl_1/2008 Nov 21st, 2018 – Introduction: Bortezomib-containing regimens (BCRs) have been the standard frontline approach for the treatment of transplant ineligible multiple myeloma (TIMM) patients in Canada for many years. Based on recent randomized clinical trial results lenalidomide and dexamethasone (Ld) has become another provincially funded option in Canada in the same therapeutic space. We aimed to compare the effe… http://www.bloodjournal.org/content/132/Suppl_1/3235 Nov 21st, 2018 – Introduction Multiple myeloma (MM) can be associated with paraskeletal (PP) or extramedullary (EMP) plasmocytomas (PL). Although PLs are relatively frequent, even at diagnosis, our knowledge on the subject mainly relies on small case series or single center experiences. Remarkably, little is known regarding the role of new drugs on MM with PL. Aim To perform a meta-analysis of 8 EMN-GIMEMA stud… http://www.bloodjournal.org/content/132/Suppl_1/3216 Nov 21st, 2018 – Selinexor (KPT-330) is a selective inhibitor of nuclear export (SINE) which specifically targets XPO1 (Exportin 1)-mediated nuclear export, leading to increased nuclear retention of major tumor suppressor proteins and inducing selective apoptosis in cancer cells. Several phase I and II clinical trials demonstrate evidence of anti-cancer activity of Selinexor in solid tumors (i.e metastatic pros… http://www.bloodjournal.org/content/132/Suppl_1/840 Nov 21st, 2018 – Background: Multiple myeloma (MM) is the most common hematologic malignancy in blacks with more than twice the incidence of non-black populations in national registry data. Prior studies have shown that blacks present with MM at an earlier age and have improved survival compared to non-blacks, contrary to the pattern in most malignancies. These findings have been theorized due to the effects of… http://www.bloodjournal.org/content/132/Suppl_1/3283 Nov 21st, 2018 – BACKGROUND & METHODS Cfz/Dex is a standard of care in relapsed MM, and renal impairment is a poor prognostic factor. The ALLG MM16 trial was initiated to assess the feasibility of treating patients (pts) who have significant RI (eGFR 15 – 40 ml/min) with Cfz/Dex, and to determine whether an early reduction in serum free light chains (SFLC), with a short half-life, could predict renal outcome. A… http://www.bloodjournal.org/content/132/Suppl_1/3302 Nov 21st, 2018 – Background: The incorporation of modern day induction regimens, autotransplant and continuous maintenance has resulted in better long-term outcomes for myeloma patients. Experience and trials demonstrated that by prolonging 1st progression-free survival (PFS1) and pushing the relapse farther, we can gain the OS advantage (McCarthy et al NEJM 2012). Unfortunately, a subgroup of patients fail to … http://www.bloodjournal.org/content/132/Suppl_1/3162 Nov 21st, 2018 – Introduction: HIV infection and the resulting immunodeficiency predispose individuals to various plasma cell disorders including reactive plasmacytosis, monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and plamacytomas. Studies have demonstrated nearly 4.5-fold increased risk of MM in HIV-infected (HIV+) individuals. Limited evidence from case reports/small serie… http://www.bloodjournal.org/content/132/Suppl_1/4491 Nov 21st, 2018 – Introduction: Several studies have shown the role of the immune system in the development of MM, but there is no systematic description of normal B-cell regeneration during treatment points. Recently, EuroFlow consortium has developed NGF panel with high sensitivity to evaluated MRD and potentially, to assess of the normal B-cell compartment of patients with MM. Aims: Here we evaluated the B ce… http://www.bloodjournal.org/content/132/Suppl_1/3208 Nov 21st, 2018 – INTRODUCTION: Despite advances in therapy, patients with relapsed AL amyloidosis die of resistant disease. New therapies are needed. siRNA directed at the constant regions of Ig light chains (LC) reduces LC mRNA and protein from patient cells, from human myeloma and AL cell lines, and in a flank plasmacytoma model with in vivo electroporation (Blood 2014;123:3440; Gene Ther 2016;23:727). To del… Αναρτήθηκε από Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174,00302841026182 στις

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The Journey So Far

The Journey So Far

« Previous post: Courtenay Wright, 1923 – 2018 The Journey So Far
Courtenay died on November 22 at 9 in the morning. He was in a hospice facility, where he’d been for a scant 53 hours. I was not with him. That is a source of pain.
On October 2, I wrote in my journal that he’d been ill, another lung infection – pneumonia? a worsening of his CPOD? – but that prednisone and antibiotics had brought him back. I wrote that I had arm-wrestled the Angel of Death, who had let me win, as he had many times in the past 17 years. “I know you could win any time you wanted,” I wrote to the Angel. “I know it’s an illusion that I have won, but I am grateful.”
The seven weeks that followed were a steady decline, just one I refused to acknowledge. Or perhaps I thought the Angel would keep letting me walk away from the table with another victory. On November 18, my poor darling lost power in his legs, but he was agitated and couldn’t stay still. I finally, on the 20th, agreed to hospice care away from the home he’d lived in for 61 years. The hope was that medication would calm his agitation and he could return to the house he loved.
The hospice nurse called and said, “I’m sorry to tell you that Courtenay made his transition.” I knew as soon as I saw the number on the screen that he had died, but the phrasing was so strange I didn’t instantly understand it. Then I screamed, “No, no, no,” even while I started pulling on outdoor clothes. Leashed the dog, texted his sons, called Marzena, who loved him like a daughter . We met in his room at the hospice center. The next 4 hours are not a blur but they are painful and private. We had to move his body out by 1 p.m. because of the rules of the hospital where the hospice is housed. We were greatly aided and supported by the hospice staff, who let us stay with him, holding him, until the last possible moment. They escorted him out with gongs, with psalms, with the Mozart clarinet concerto. I wanted to fling myself on the body and scream and tear myself apart, but could not.
We had a funeral service on the 25th, Jewish, in our home. Beautiful and overwhelming. Courtenay’s favorite poem, Mary Oliver’s “ When Death Comes. ” So true to him: “a bride, married to amazement, the bridegroom, taking the world into my arms.” My own favorite: A Valediction: Forbidding Mourning . “Our two soules, therefore, which are one, though I must go, endure not yet a breach but an expansion.” My beloved Eve read that, a heroic effort to make it through to the end without breaking down.
It turns out there is no pre-mourning. Over the last 5 years, he gradually lost many of his great capabilities, the problem-solving, the insights, the understanding of General Relativity and Quantum Mechanics and how they are at work and play in the natural world that surrounds us. He became bewildered by simple things and there was so much loss that I thought the ultimate loss would not be so devastating. There is no pre-mourning. The ultimate loss is still a grand piano that drops from the sky onto one’s head.
I have a shrine in the living room: his ashes with emblems of his loves – a photo of him with one of the dogs he adored, the Go stones for the game that was his passion, pool balls – another passion. (Two weeks before he died he did the equivalent of running the table in the arcane version of billiard-pool he and his friends played). I still need something to signify his love of ships and sailing. I figure the room is full of photons and electrons. I talk to him at the shrine.
I walk the lakefront with the dog, who was inseparable from him for four years and is as bewildered as I am. I watch the ducks in the cold water, the grey air, and take solace in knowing that I am connected to a web of nature, of plants and animals where we all keep going, putting one little webbed foot in front of the other, valiantly braving the cold.
It turns out mourning is physical. It is exhausting, but one feels it in the body. In my case, it’s a heaviness in the stomach. When I imagine going shopping, or traveling, or any of those things, the heaviness increases and tells me to stay put.
The least thing can make the chest constrict. Also I am bewildered: I want him here, but memories also stir the more recent griefs: he was the most competent man I ever knew, the most moral, the kindest, the most brilliant but in the last years he relied on me to mediate every aspect of the surrounding world. It was never a burden but it was always a grief.
I am on an express train moving at too fast a rate from the place I want to inhabit, the world where the Angel of Death let me keep winning our arm-wrestling matches. People in my house for the last 8 days interrupted my grief and I am angry that I let those precious days close to the station be taken from me.
I have always hated my legs – they look fat and wobbly. Almost every day for 47 years, Courtenay said to me, “You have beautiful legs.” At the hospice, I lay in bed with him, holding him, singing the ballads he loved. The last words he said to me were, “Your voice is lovely and your legs are beautiful.”
He never in 47 years complained of pain, despite crippling RA, a leg broken in 7 places, cancer and radiation therapy. He never wanted novocaine when getting dental work, no nerve blocks when he needed hand surgery. The last 4 days the pain was too great for his stoic heroic heart. I should have stayed with him, holding him, but I did not. I was the bustling Martha, trying to set up in-home care, imagining he would come back. I was walking the dog and writing emails and not knowing I should not have left his side. That is a pain I can hardly bear.
The journey so far. This entry was posted on Friday, December 14th, 2018 at 9:05 pm. You can follow any responses to this entry through the RSS 2.0 feed. You can skip to the end and leave a response. Pinging is currently not allowed. Search

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Pulmicort Flexhaler (Budesonide Inhalation Powder) – updated on RxList

<h1>Pulmicort Flexhaler (Budesonide Inhalation Powder) – updated on RxList</h1>

Pulmicort Flexhaler (Budesonide Inhalation Powder) – updated on RxList

LMICORT dry powder inhaler with an incidence of ≥ 1% in the budesonide group and were more common than in the placebo group:
1-3%: neck pain , syncope , abdominal pain , dry mouth, vomiting, weight gain, fracture, myalgia , hypertonia , migraine , ecchymosis , insomnia , infection, taste perversion, voice alteration.
dyspepsia , gastroenteritis, nausea, and back pain, compared with doses of 400 mcg twice daily.
usitis, headache, oral candidiasis, pain, asthenia , dyspepsia, arthralgia , cough increased, nausea and rhinitis .
: immediate and delayed hypersensitivity reactions including anaphylactic reaction, angioedema , bronchospasm, rash , contact dermatitis , urticaria , and cough, wheezing or bronchospasm in patients with severe milk protein hypersensitivity [see WARNINGS AND PRECAUTIONS and CONTRAINDICATIONS ]
: symptoms of hypocorticism and hypercorticism [see WARNINGS AND PRECAUTIONS ]
: cataracts, glaucoma, increased intraocular pressure [see WARNINGS AND PRECAUTIONS ]
: psychiatric symptoms including psychosis , depression , aggressive reactions, irritability, nervousness, restlessness, and anxiety
: throat irritation
: skin bruising
metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole , a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the co-administration of PULMICORT FLEXHALER (budesonide inhalation powder) with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin , indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see WARNINGS and PRECAUTIONS ]. & Precautions
PRECAUTIONS section.
pharynx with Candida albicans has occurred in patients treated with PULMICORT FLEXHALER. When such an infection develops, it should be treated with appropriate local or systemic (i.e. oral antifungal ) therapy while treatment with PULMICORT FLEXHALER continues, but at times, therapy with PULMICORT FLEXHALER (budesonide inhalation powder) may need to be interrupted. Patients should rinse the mouth after inhalation of PULMICORT FLEXHALER.
shortness of breath . When prescribing PULMICORT FLEXHALER, the physician must also provide the patient with an inhaled, short-acting beta2-agonist (e.g. albuterol ) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of PULMICORT FLEXHALER (budesonide inhalation powder) .
contact dermatitis , urticaria , angioedema , and bronchospasm have been reported with use of PULMICORT FLEXHALER. Discontinue PULMICORT FLEXHALER if such reactions occur [see CONTRAINDICATIONS and ADVERSE REACTIONS ].
lactose , which contains trace levels of milk proteins. It is possible that cough, wheezing, or bronchospasm may occur in patients who have a severe milk protein allergy . [see CONTRAINDICATIONS and ADVERSE REACTIONS , Post-marketing Experience ].
immune system are more susceptible to infection than healthy individuals. Chicken pox and measles , for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular ( IG ) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information .) If chicken pox develops, treatment with antiviral agents may be considered. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension.
leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥ 5.0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%), compared to patients treated with non-corticosteroid asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.
quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral or parasitic infections, or ocular simplex.
pituitary -adrenal (HPA) function.
prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.
trauma , surgery, or infection (particularly gastroenteritis ) or other conditions associated with severe electrolyte loss. Although PULMICORT FLEXHALER (budesonide inhalation powder) may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.
stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
is during therapy with PULMICORT FLEXHALER (budesonide inhalation powder) . Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [ PEF ]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude , weakness, nausea and vomiting, and hypotension .
rhinitis , conjunctivitis , eczema , arthritis , eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression ) despite maintenance or even improvement of respiratory function.
nction than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of PULMICORT FLEXHALER (budesonide inhalation powder) in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose . Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing PULMICORT FLEXHALER (budesonide inhalation powder) . Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT FLEXHALER should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
budesonide may occur [see DRUG INTERACTIONS , CLINICAL PHARMACOLOGY ].
bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis , post menopausal status, tobacco use, advance age, poor nutrition , or chronic use of drugs that can reduce bone mass (e.g, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.
DOSAGE AND ADMINISTRATION , Use in Specific Populations ].
ased intraocular pressure , and cataracts have been reported following the long-term administration of inhaled corticosteroids, including budesonide. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
vasculitis consistent with Churg-Strauss syndrome , a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Physicians should be alert to eosinophilia , vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established.
FDA Approved Patient Labeling .
Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e. oral) antifungal therapy while still continuing therapy with PULMICORT FLEXHALER (budesonide inhalation powder) , but at times therapy with PULMICORT FLEXHALER (budesonide inhalation powder) may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised. [see WARNINGS AND PRECAUTIONS ] or more inhalations than usual of inhaled, short-acting beta2-agonists
WARNINGS AND PRECAUTIONS ]
CONTRAINDICATIONS , WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS ].
CONTRAINDICATIONS ].
immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see WARNINGS AND PRECAUTIONS ]
curred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to PULMICORT FLEXHALER (budesonide inhalation powder) [see WARNINGS AND PRECAUTIONS ].
WARNINGS AND PRECAUTIONS ].
WARNINGS AND PRECAUTIONS ].
WARNINGS AND PRECAUTIONS ].
sense the presence of any medication entering their lungs when inhaling from PULMICORT FLEXHALER (budesonide inhalation powder) . This lack of sensation does not mean that they did not get the medication. They should not repeat their inhalation even if they did not feel the medication when inhaling [see PATIENT INFORMATION ].
² basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.1 and 0.2 times, respectively, the maximum recommended daily inhalation dose in adults and children 6 to 17 years of age, on a mcg/m² basis) and in female rats at oral doses up to 50 mc/kg (approximately 0.3 times the maximum recommended daily inhalation doses in adults and children 6 to 17 years of age, respectively, on a mcg/m² basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.3 times the maximum recommended daily inhalation dose in adults and children 6 to 17 years of age, respectively, on a mcg/m² basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.3 times the maximum recommended daily inhalation doses in adults and children 6 to 17 years of age on a mcg/m² basis). The concurrent reference corticosteroids (prednisone and triamcinolone acetonide) in these two studies showed similar findings.
carcinogenic effect when budesonide was administered orally for 91 weeks to mice at doses up to 200 mcg/kg/day (approximately 0.6 and 0.7 times, respectively the maximum recommended daily inhalation dose in adults and children 6 to 17 years of age on a mcg/m² basis).
Salmonella /microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive test in Drosophila melanogaster , and DNA repair analysis in rat hepatocyte culture.
² basis).
² basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 mcg/kg (approximately 0.03 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis). : Pregnancy Category B
prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period ), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs. 3.3, respectively).
fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, PULMICORT FLEXHALER (budesonide inhalation powder) should be used during pregnancy only if clearly needed.
² basis and at a subcutaneous dose inrats that was approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis. No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to approximately equivalent to the maximum recommended daily inhalation dose in adults on a mcg/m² basis.
physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.
CLINICAL PHARMACOLOGY , Pharmacokinetics, Special Populations, Nursing Mothers ]. No studies have been conducted in breastfeeding women specifically with PULMICORT FLEXHALER; however, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar. PULMICORT FLEXHALER (budesonide inhalation powder) should be used in nursing women only if clinically appropriate. Prescribers should weigh the known benefits of breastfeeding for the mother and the infant against the potential risks of minimal budesonide exposure in the infant. Dosing considerations include prescription or titration to the lowest clinically effective dose and use of PULMICORT FLEXHALER (budesonide inhalation powder) immediately after breastfeeding to maximize the time interval between dosing and breastfeeding to minimize infant exposure. However, in general, PULMICORT FLEXHALER (budesonide inhalation powder) use should not delay or interfere with infant feeding.
Clinical Studies ]. Efficacy results in this age group were similar to those observed in patients 18 years and older. There were no obvious differences in the type or frequency of adverse events reported in this age group compared with patients 18 years of age and older.
laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids including the impact on final adult height are unknown. The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.
puberty during the course of the study.
metered-dose inhaler in doses up to 1200 mcg/day (mean daily dose 620 mcg/day) to 216 pediatric patients (age 3 to 11 years) for 2 to 6 years had no significant effect on statural growth compared with non-corticosteroid therapy in 62 matched control patients. However, the long-term effect of inhaled budesonide on growth is not fully known.
FLEXHALER (budesonide inhalation powder) , should be monitored (eg, via stadiometry). If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained. To minimize the systemic effects of inhaled corticosteroids, including PULMICORT FLEXHALER (budesonide inhalation powder) , each patient should be titrated to the lowest dose that effectively controls his/her asthma [see DOSAGE AND ADMINISTRATION ].
closely monitored. & Contraindications
WARNINGS AND PRECAUTIONS , Hypercorticism and Adrenal Suppression ]. Another budesonide-containing dry powder inhaler at 3200 mcg daily administered for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH.
² basis). There were no deaths following the administration of an inhalation dose of 68 mg/kg in rats (approximately 380 times the maximum recommended daily inhalation dose in adults and approximately 450 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m² basis). The minimal oral lethal dose was 200 mg/kg in mice (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m² basis) and less than 100 mg/kg in rats (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age based on a mcg/m² basis).
asymptomatic . The use of excessive doses (up to 6400 mcg daily) for prolonged periods showed systemic corticosteroid effects such as hypercorticism. WARNINGS AND PRECAUTIONS , DESCRIPTION ].
corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus assay. The clinical significance of this is unknown.
pathogenesis of asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine , eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
below ).
adenosine monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain.
1 following inhaled allergen challenge.
: The effects of inhaled budesonide on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 905 adults and 404 pediatric patients with asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by cosyntropin (ACTH) stimulation test, remained intact with inhaled budesonide treatment at recommended doses. For adult patients treated with 100, 200, 400, or 800 mcg twice daily for 12 weeks, 4%, 2%, 6%, and 13% respectively, had an abnormal stimulated cortisol response (peak cortisol < 14.5 mcg/dL assessed by liquid chromatography following short-cosyntropin test) as compared with 8% of patients treated with placebo. Similar results were obtained in pediatric patients. In another study in adults, doses of 400, 800 and 1600 mcg of inhaled budesonide twice daily for 6 weeks were examined; 1600 mcg twice daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while 10 mg prednisone resulted in a 35% reduction. In this study, no patient taking doses of 400 and 800 mcg twice daily met the criterion for an abnormal stimulated cortisol response (peak cortisol < 14.5 mcg/dL assessed by liquid chromatography) following ACTH infusion. An open-label, long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal effect on the HPA axis (both basal and stimulated plasma cortisol) of inhaled budesonide when administered at doses ranging from 100 to 800 mcg twice daily. In patients who had previously been oral steroid -dependent, use of inhaled budesonide at doses ranging from 100 to 800 mcg twice daily was associated with higher stimulated cortisol response compared with baseline following 1 year of therapy.
ved in about 1 to 2 hours and the absolute systemic availability was 6-13%. In contrast, most of budesonide delivered to the lungs is systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lungs (as assessed by plasma concentration method and using a different budesonide containing dry-powder inhaler) with an absolute systemic availability of 39% of the metered dose. Peak steady-state plasma concentrations of budesonide delivered from PULMICORT FLEXHALER in adults with asthma (n=39) occurred at approximately 10 minutes post-dose and averaged 0.6 and 1.6 nmol/L at doses of 180 mcg once daily and 360 mcg twice daily, respectively.
red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.
α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations.
postpartum . Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breastfeeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels ( < 0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see Use In Specific Populations , Nursing Mothers ].
: Ketoconazole, a strong inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS ].
: At recommended doses, cimetidine , a nonspecific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.
teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.3 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis) and at a subcutaneous dose of 500 mcg/kg in rats (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis). No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to 250 mcg/kg (approximately equivalent to the maximum recommended daily inhalation dose in adults on a mcg/m² basis).
udy 2 evaluated PULMICORT FLEXHALER (budesonide inhalation powder) 90 mcg, 2 inhalations once daily or 4 inhalations twice daily, PULMICORT TURBUHALER 200 mcg, 1 inhalation once daily or 2 inhalations twice daily, and placebo in pediatric patients aged 6 to 17 years with mild to moderate asthma. Both of the studies had a 2-week placebo treatment run-in period followed by a 12-week randomized treatment period. The primary endpoint was the difference between baseline and the mean of the treatment-period FEV 1 (adults) or FEV 1 % predicted (children). ≥ 18 years of age and older (Study 1)
≥ 18 to 80 years with mild-to-moderate asthma (mean baseline % predicted FEV 1 64.3%) whose symptoms were previously controlled on inhaled corticosteroids. Mean change from baseline in FEV 1 in the PULMICORT FLEXHALER (budesonide inhalation powder) 180 mcg, 2 inhalations twice-daily group was 0.28 liters, as compared to 0.10 liters in the placebo group (p < 0.001). Secondary endpoints of morning and evening peak expiratory flow rate, daytime asthma symptom severity, nighttime asthma symptom severity, daily rescue medication use, and the percentage of patients who met predefined asthma related withdrawal criteria showed differences from baseline favoring PULMICORT FLEXHALER (budesonide inhalation powder) over placebo (p < 0.001). 1 (L) otnote : PULMICORT TURBUHALER; a different PULMICORT DPI Statistical model is analysis of covariance with treatment and region (US/Asia) as factors and the baseline value as the covariate.
1 84.9%). The study population included patients previously treated with inhaled corticosteroids for no more than 30 days before the study began (4%) and patients who were naïve to inhaled corticosteroids (96%). Mean change from baseline in % predicted FEV 1 during the 12-week treatment period in the PULMICORT FLEXHALER (budesonide inhalation powder) 90 mcg, 4 inhalations twice daily treatment group was 5.6 compared with 0.2 in the placebo group (p < 0.001). Secondary endpoints of morning and evening PEF showed differences from baseline favoring PULMICORT FLEXHALER (budesonide inhalation powder) over placebo (p < 0.001). 1

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Treatment for Allergies

Treatment for Allergies

Allergy Symptoms & Treatments : How to Cure Dust Allergies Treatment for Allergies Allergy Drugs
Besides nasal sprays that relieve sinus-related symptoms, there are medications that can help reduce your body’s reaction to allergens. These drugs, both OTC and prescription, can be taken as liquids or pills.
Common allergy medicines include: Antihistamines
Antihistamines work by blocking the effects of histamine (a chemical in the body that can cause allergy symptoms). They’re sometimes combined with other types of drugs.
Examples of antihistamines include:
Common side effects of antihistamines include: Drowsiness or sleepiness Dry mouth, nose, or throat Increased appetite and weight gain Upset stomach Changes in vision Feeling nervous, excited, or irritable
You may need to avoid certain foods, such as grapefruit and grapefruit juice, while taking an antihistamine because they can affect how these drugs work in your body. Alcohol may worsen certain side effects.
Talk to your doctor about any symptoms or concerns you may have. Decongestants
These medications relieve congestion by shrinking swollen nasal tissues and blood vessels. They are often prescribed along with antihistamines.
Examples of decongestants include: Mast Cell Stabilizers
These medications block the release of immune system chemicals (histamine, leukotriene) that trigger allergic reactions of the eyes (allergic conjunctivitis) or nasal passageway. They are better at preventing than treating allergic symptoms, so they are given to patients with seasonal allergies starting about two weeks before allergy season begins.
Examples of mast cell stabilizers include: Alomide (lodoxamide) — eye drops Nasalcrom (cromolyn sodium) — nasal spray Steroids
These drugs can help reduce inflammation in the nasal passages, lungs, and skin. Steroid use can cause a wide range of side effects and needs to be closely monitored by your doctor.
Prednisone is a corticosteroid, or man-made form of the steroid that the body produces to fight illnesses and injuries. It is prescribed alone or in combination with other medication to treat severe allergic reactions and many other conditions. It is given in liquid or tablet form. (5) Leukotriene Modifiers
Leukotrienes are chemicals the body releases as a response to allergens. They can cause airway constriction, inflammation in the lungs, and increased mucus production.
Leukotrine modifiers are a class of drugs that work by blocking the actions of leukotrienes in the body. They are used to treat symptoms of asthma and, in the case of the drug Singulair (montelukast), allergic rhinitis. Anti-Immunoglobulin E (IgE) Therapy
Xolair (omalizumab) helps decrease allergic responses in the body by reducing the number of Ige (immunoglobulin E) antibodies the immune system produces in response to an allergen. (6)
It is used to treat moderate to severe asthma that is caused by allergies in adults and children who are at least 6 years old.
The drug is injected under the skin, and it is usually given every two or four weeks. Epinephrine
Epinephrine is used to treat anaphylaxis — a severe, life-threatening allergic reaction — until emergency treatment can be administered.
Anaphylactic reactions are commonly caused by Foods, such as peanuts, tree nuts, wheat, fish, milk, and eggs Medication, especially penicillin and stings Latex
Prescribed by your doctor, epinephrine comes as a single dose in an auto-injector (such as an EpiPen). An injection of epinephrine quickly improves breathing, stimulates the heart, raises dropping blood pressure, reverses hives, and reduces swelling of the face, lips, and throat. Video: Allergies to Cats & Recurring Sinus Infections : Treating Allergies Treatment for Allergies images 2019 year – Treatment for Allergies pictures Treatment for Allergies recommendations photo Treatment for Allergies photo Treatment for Allergies new picture pictures Treatment for Allergies Watch Treatment for Allergies video Discussion on this topic: Treatment for Allergies , treatment-for-allergies/ , treatment-for-allergies/ Related News

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Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Resectable Gastric Cancer

<h1>Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Resectable Gastric Cancer</h1>

Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Resectable Gastric Cancer

You have reached the maximum number of saved studies (100). Please remove one or more studies before adding more. Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Resectable Gastric Cancer The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. ClinicalTrials.gov Identifier: NCT03776487 Recruitment Status : Not yet recruiting First Posted : December 14, 2018 Last Update Posted : December 14, 2018 Information provided by (Responsible Party): M.D. Anderson Cancer Center Study Description Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Brief Summary: This pilot phase I/II trial studies the side effects and how well nivolumab and ipilimumab in combination with chemotherapy and radiation therapy work in treating patients with gastric cancer that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as oxaliplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Intensity-modulated radiation therapy uses thin beams of radiation of different strengths aimed at the tumor from many angles. This type of radiation therapy may reduce the damage to healthy tissue near the tumor. Giving nivolumab, ipilimumab, chemotherapy and radiation therapy may work better in treating patients with gastric cancer. Condition or disease Intervention/treatment Phase Clinical Stage 0 Gastric Cancer AJCC v8 Clinical Stage 0 Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage I Gastric Cancer AJCC v8 Clinical Stage I Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IIB Gastric Cancer AJCC v8 Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8 Clinical Stage IVA Gastric Cancer AJCC v8 Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Gastric Adenocarcinoma Localized Gastric Carcinoma Localized Gastroesophageal Junction Adenocarcinoma Pathologic Stage 0 Gastric Cancer AJCC v8 Pathologic Stage 0 Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage I Gastric Cancer AJCC v8 Pathologic Stage IA Gastric Cancer AJCC v8 Pathologic Stage IA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IB Gastric Cancer AJCC v8 Pathologic Stage IB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IC Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIA Gastric Cancer AJCC v8 Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIB Gastric Cancer AJCC v8 Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IIIA Gastric Cancer AJCC v8 Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8 Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8 Drug: Fluorouracil Radiation: Intensity-Modulated Radiation Therapy Biological: Ipilimumab Biological: Nivolumab Drug: Oxaliplatin Procedure: Therapeutic Conventional Surgery Phase 1 Phase 2 Detailed Description: PRIMARY OBJECTIVES: I. To evaluate the safety and toxicity profile of intravenous nivolumab in combination with ipilimumab after standard chemotherapy and followed by intravenous nivolumab in combination with fluoropyrimidine and intensity-modulated radiation therapy (IMRT) for the treatment of localized gastroesophageal junction (GEJ) and/or gastric cancer. SECONDARY OBJECTIVES: I. To assess the efficacy of double checkpoint inhibition (nivolumab + ipilimumab) followed by nivolumab plus chemoradiation. II. To assess the overall safety and tolerability of adjuvant nivolumab in subjects with resected GEJ or gastric cancer. III. To evaluate disease free survival (DFS). IV. To explore changes in tumor stroma profile before and after immunotherapy and radiation therapy. V. To bank tumor and blood specimen for future correlative analysis, including, but not limited to, biomarker analysis. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin intravenously (IV) over 2 hours and fluorouracil IV over 48 hours on day 1. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning course 4, patients also receive fluorouracil IV continuously for 5 days per week and undergo 25 fractions of IMRT for 5 weeks. Patients undergo surgical resection 5-7 weeks after completing radiation therapy. Within 8-12 weeks post-surgery, patients with residual disease may receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 8 courses (16 weeks) then every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 and 84 days, every 12 weeks for 2 years, then every 6-12 months for up to 3 years. Study Design Go to
Treatment Official Title: Pilot Study of Dual Checkpoint Inhibition Followed by Immuno-Chemoradiation in Patients With Resectable Gastric Adenocarcinoma (Concept ID 2016-NIV-0551) Estimated Study Start Date : Arms and Interventions Go to
Intervention/treatment Experimental: Treatment (chemotherapy, immunotherapy, IMRT) INDUCTION CHEMOTHERAPY: Patients receive oxaliplatin IV over 2 hours and fluorouracil IV over 48 hours on day 1. Treatment repeats every 14 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment with nivolumab repeats every 2 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning course 4, patients also receive fluorouracil IV continuously for 5 days per week and undergo 25 fractions of IMRT for 5 weeks. Patients undergo surgical resection 5-7 weeks after completing radiation therapy. Within 8-12 weeks post-surgery, patients with residual disease may receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 8 courses (16 weeks) then every 4 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Drug: Fluorouracil Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody BMS-734016 Undergo partial or total gastrectomy and lymphadenectomy Outcome Measures Go to Primary Outcome Measures : Incidence of adverse events [ Time Frame: Up to 30 days ] The Bayesian method of Thall, Simon and Estey will be implemented for toxicity monitoring. Safety data will be summarized using frequency tables by organ system, grade and attribution for the neoadjuvant period and adjuvant period separately. Secondary Outcome Measures : Response rates [ Time Frame: Up to 5 years ] Response rates will be estimated along with the corresponding exact 95% confidence interval. Incidence of adverse events in patients with resected gastroesophageal junction (GEJ) or gastric cancer [ Time Frame: Up to 5 years ] The Bayesian method of Thall, Simon and Estey will be implemented for toxicity monitoring. Safety data will be summarized using frequency tables by organ system, grade and attribution for the neoadjuvant period and adjuvant period separately. Disease-free survival [ Time Frame: From the date of surgery until disease relapse or death, whichever occurred first, assessed up to 5 years ] Will be estimated using the method of Kaplan and Meier. Eligibility Criteria Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: Criteria Inclusion Criteria: Subjects must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study. All subjects must have localized/eligible for surgery gastric cancer (GC) or GEJ carcinoma type III, with negative peritoneal washing. Subjects must have histologically confirmed predominant adenocarcinoma. The documentation of GEJ involvement can include biopsy, endoscopy, or imaging. Subject must be previously untreated with systemic treatment (including HER 2 inhibitors) given as primary therapy for advanced or metastatic disease. No prior neoadjuvant chemotherapy, immunotherapy, radiotherapy and/or chemoradiotherapy are permitted. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days of treatment initiation). Platelets >=100,000/mcL (within 28 days of treatment initiation). Hemoglobin >= 9 g/dL or > 5.6 mmol/L; if patient is not actively bleeding and has hemoglobin of = 9g/dL (within 28 days of treatment initiation). Serum creatinine = 60 mL/min for subjects with creatinine levels > 1.5 x institutional ULN (measured via 24-hour urine collection) (within 28 days of treatment initiation). Creatinine clearance should be calculated per institutional standard. Serum total bilirubin =< 1.5 X ULN (1.5 mg/dL or 25.65 umol/L) OR direct bilirubin < ULN for subjects with total bilirubin levels < 1.5 X ULN. Except patients with Gilbert's disease (< 3 X ULN) (within 28 days of treatment initiation). Aspartate aminotransferase AST (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR = 3 mg/dL (within 28 days of treatment initiation). Prothrombin Time (PT) < 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time PTT is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin Time (aPTT) 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally. White blood cell (WBC) < 2000/uL. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g. hepatitis B surface antigen (HBsAg Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if hepatitis C virus- ribonucleic acid [HCV-RNA] negative). History of allergy or hypersensitivity to study drug components. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. Patients with serious or uncontrolled medical disorders. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. Contacts and Locations Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03776487 Contacts

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