ASH Clinical News September 2017 New | Page 46

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functional impairment , and quality of life
Investigators also completed case reports during the comprehensive care visit .
The researchers noted discrepancies between patient- and sitereported measures of functional disability ( such as restricted work , school , and recreational activities
because of pain , loss of motion , and weakness ), “ suggesting a potential underestimation of patients ’ functional status by HTC staff , or potential discrepancies in the perception of function between patients and investigators .”
Many patients ( 56 %) reported that they did not receive routine infusions , with some ( 30 %) having never received routine infusions .
“ A low rate of prophylaxis was observed , considering the prevalence of severe hemophilia ( 71 %),” the authors reported . Thirty percent never received prophylaxis , 32 percent received prophylaxis for less than half of their lives , and only 47 percent of those with both acute and chronic pain were currently receiving prophylaxis . “ The lack of prophylaxis ,
particularly if it occurred during childhood and adolescence , may have affected participants ’ development of joint damage and chronic pain ,” they observed .
During the six months prior to completing the survey , most patients ( 85 %) experienced pain . Twenty percent reported experiencing acute pain only , 34 percent reported experiencing chronic
Nervous system disorders : Peripheral neuropathy ( 17 %, 12 %), Dizziness ( 12 %, 9 %), Headache ( 8 %, 5 %), Tremor ( 6 %, 1 %), Depressed level of consciousness ( 2 %, 0 %) a ; Metabolism and nutrition disorders : Decreased appetite ( 13 %, 8 %), Hypokalemia ( 9 %, 8 %) a , Hypocalcemia ( 4 %, 6 %) a ; Skin and subcutaneous tissue disorders : Rash ( 8 %, 1 %), Pruritus ( 7 %, 3 %), Hyperhidrosis ( 5 %, 1 %); Investigations : Neutrophil count decreased ( 5 %, 1 %), Platelet count decreased ( 3 %, 2 %) a , White blood cell count decreased ( 3 %, 1 %) a , Alanine aminotransferase increased ( 2 %, 1 %) a , Aspartate aminotransferase increased ( 1 %, 1 %) a , Lymphocyte count decreased ( 1 %, 1 %) a ; Renal and urinary disorders : Renal failure ( 10 %, 12 %) a ; Injury , poisoning and procedural complications : Femur fracture b ( 2 %, 1 %) a ; Reproductive system and breast disorders : Pelvic pain ( 2 %, 2 %) a .
In Trial 2 , Grade 3 / 4 at least one adverse reaction was reported in 86 % of patients treated with POMALYST + Low-dose Dex ( N = 300 ) and 85 % with High-dose Dex ( N = 150 ).
Grade 3 / 4 Adverse Reactions ≥1 % in POMALYST + Low-dose Dex arm , and at least 1 % point higher than the High-dose-Dex arm , respectively , included : Blood and lymphatic system disorders : Neutropenia b ( 48 %, 16 %), Thrombocytopenia ( 22 %, 26 %) a , Leukopenia ( 9 %, 3 %), Febrile neutropenia b ( 9 %, 0 %); General disorders and administration site conditions : Fatigue and asthenia ( 9 %, 12 %) a , Pyrexia b ( 3 %, 5 %) a , Edema peripheral ( 1 %, 2 %) a , Pain ( 2 %, 1 %); Infections and infestations : Upper respiratory tract infection b ( 3 %, 1 %), Pneumonia b ( 16 %, 10 %), Neutropenic sepsis b ( 1 %, 0 %); Gastrointestinal disorders : Diarrhea ( 1 %, 1 %) a , Constipation ( 2 %, 0 %), Nausea ( 1 %, 1 %) a , Vomiting ( 1 %, 0 %); Musculoskeletal and connective tissue disorders : Back pain b ( 5 %, 4 %), Bone pain b ( 7 %, 5 %), Muscle spasms ( 0 %, 1 %) a , Arthralgia ( 1 %, 1 %) a , Pain in extremity ( 2 %, 0 %); Respiratory , thoracic and mediastinal disorders : Dyspnea b ( 6 %, 5 %), Cough ( 1 %, 1 %) a , Chronic obstructive pulmonary disease b ( 1 %, 0 %); Nervous system disorders : Peripheral neuropathy ( 2 %, 1 %) a , Dizziness ( 1 %, 1 %) a , Headache ( 0 %, 0 %) a , Tremor ( 1 %, 0 %) a , Depressed level of consciousness ( 1 %, 0 %); Metabolism and nutrition disorders : Decreased appetite ( 1 %, 1 %) a , Hypokalemia ( 4 %, 3 %), Hypocalcemia ( 2 %, 1 %); Skin and subcutaneous tissue disorders : Rash ( 1 %, 0 %), Pruritus ( 0 %, 0 %) a , Hyperhidrosis ( 0 %, 0 %) a ; Investigations : Neutrophil count decreased ( 5 %, 1 %), Platelet count decreased ( 3 %, 1 %), White blood cell count decreased ( 3 %, 0 %), Alanine aminotransferase increased ( 2 %, 0 %), Aspartate aminotransferase increased ( 1 %, 0 %), Lymphocyte count decreased ( 1 %, 0 %); Renal and urinary disorders : Renal failure ( 6 %, 5 %); Injury , poisoning and procedural complications : Femur fracture b ( 2 %, 1 %); Reproductive system and breast disorders : Pelvic pain ( 1 %, 0 %). a Percentage did not meet the criteria to be
considered as an adverse reaction for POMALYST for that category of event ( i . e ., all adverse events or Grade 3 or 4 adverse events ). b
Serious adverse reactions were reported in at least 3 patients in the POM + Low-dose Dex arm , AND at least 1 % higher than the High-dose-Dex arm percentage . Data cutoff : 01 March 2013
Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma , not described above , and considered important :
Cardiac disorders : Myocardial infarction , Atrial fibrillation , Angina pectoris , Cardiac failure congestive Ear and labyrinth disorders : Vertigo Gastrointestinal disorders : Abdominal pain General disorders and administration site conditions : General physical health deterioration , Non-cardiac chest pain , Multi-organ failure Hepatobiliary disorders : Hyperbilirubinemia Infections and infestations : Pneumocystis jiroveci pneumonia , Respiratory syncytial virus infection , Neutropenic sepsis , Bacteremia , Pneumonia respiratory syncytial viral , Cellulitis , Urosepsis ,
Septic shock , Clostridium difficile colitis , Pneumonia streptococcal , Lobar pneumonia , Viral infection , Lung infection Investigations : Alanine aminotransferase increased , Hemoglobin decreased Injury , poisoning and procedural complications : Fall , Compression fracture , Spinal compression fracture Metabolism and nutritional disorders : Hyperkalemia , Failure to thrive Nervous System disorders : Depressed level of consciousness , Syncope Psychiatric disorders : Mental status change Renal and urinary disorders : Urinary retention , Hyponatremia Reproductive system and breast disorders : Pelvic pain Respiratory , thoracic , and mediastinal disorders : Interstitial lung disease , Pulmonary embolism , Respiratory failure , Bronchospasm Vascular disorders : Hypotension
6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of POMALYST . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure : Pancytopenia , tumor lysis syndrome , allergic reactions ( e . g ., angioedema , urticaria ), elevated liver enzymes , hepatic failure ( including fatal cases ), hepatitis B virus reactivation , herpes zoster , gastrointestinal hemorrhage , basal cell carcinoma and squamous cell carcinoma of the skin .
7 DRUG INTERACTIONS 7.1 Drugs That Affect Pomalidomide Plasma Concentrations Pomalidomide is primarily metabolized by CYP1A2 and CYP3A4 . Pomalidomide is also a substrate for P-glycoprotein ( P-gp ).
CYP1A2 inhibitors : In healthy volunteers , co-administration of fluvoxamine , a strong CYP1A2 inhibitor , increased C max and AUC of pomalidomide by 24 % and 125 % respectively . Increased pomalidomide exposure increases the risk of exposure related toxicities .
Avoid co-administration of strong CYP1A2 inhibitors ( e . g . ciprofloxacin and fluvoxamine ) [ see Dosage and Administration ( 2.3 )]. If co-administration is unavoidable , reduce the POMALYST dose [ see Dosage and Administration ( 2.3 )].
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy as well as female partners of male patients who are exposed to POMALYST . This registry is also used to understand the root cause for the pregnancy . Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436 .
Risk Summary Based on the mechanism of action and findings from animal studies , POMALYST can cause embryofetal harm when administered to a pregnant female and is contraindicated during pregnancy [ see Boxed Warning , Contraindications ( 4 ), and Warnings and Precautions ( 5.1 )].
POMALYST is a thalidomide analogue . Thalidomide is a human teratogen , inducing a high frequency of severe and life-threatening birth defects such as amelia ( absence of limbs ), phocomelia ( short limbs ), hypoplasticity of the bones , absence of bones , external ear abnormalities ( including anotia , micropinna , small or absent external auditory canals ), facial palsy , eye abnormalities ( anophthalmos , microphthalmos ), and congenital heart defects . Alimentary tract , urinary tract , and genital malformations have also been documented , and mortality at or shortly after birth has been reported in about 40 % of infants .
Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis . Pomalidomide crossed the placenta after administration to pregnant rabbits [ see Data ]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug , the patient should be apprised of the potential risk to a fetus .
If pregnancy does occur during treatment , immediately discontinue the drug . Under these conditions , refer patient to an obstetrician / gynecologist experienced in reproductive toxicity for further evaluation and counseling . Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436 .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown . The estimated background risk in the U . S . general population of major birth defects is 2 % -4% and of miscarriage is 15 % -20% of clinically recognized pregnancies .
Data Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis .
In rats , pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg / kg / day . Malformations or absence of urinary bladder , absence of thyroid gland , and fusion and misalignment of lumbar and thoracic vertebral elements ( vertebral , central , and / or neural arches ) were observed at all dose levels . There was no maternal toxicity observed in this study . The lowest dose in rats resulted in an exposure ( AUC ) approximately 85-fold of the human exposure at the recommended dose of 4 mg / day . Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses .
In rabbits , pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg / kg / day . Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg / kg / day . Additional malformations observed at 250 mg / kg / day included anomalies in limbs ( flexed and / or rotated foreand / or hindlimbs , unattached or absent digit ) and associated skeletal malformations ( not ossified metacarpal , misaligned phalanx and metacarpal , absent digit , not ossified phalanx , and short not ossified or bent tibia ), moderate dilation of the lateral ventricle in the brain , abnormal placement of the right subclavian artery , absent intermediate lobe in the lungs , low-set kidney , altered liver morphology , incompletely or not ossified pelvis , an increased average for supernumerary thoracic ribs , and a reduced average for ossified tarsals . No maternal toxicity was observed at the low dose ( 10 mg / kg / day ) that resulted in cardiac anomalies in fetuses ; this dose resulted in an exposure ( AUC ) approximately equal to that reported in humans at the recommended dose of 4 mg / day . Additional embryo-fetal toxicity included increased resorption .
Following daily oral administration of pomalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits , fetal plasma pomalidomide concentrations were approximately 50 % of the maternal C max at all dosages ( 5 to 250 mg / kg / day ), indicating that pomalidomide crossed the placenta .
8.2 Lactation Risk Summary There is no information regarding the presence of pomalidomide in human milk , the effects of POMALYST on the breastfed infant , or the effects of POMALYST on milk production . Pomalidomide was excreted in the milk of lactating rats [ see Data ]. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from POMALYST , advise a nursing woman to discontinue breastfeeding during treatment with POMALYST .