|
|
|
CLINICAL NEWS |
|
The patients ( mean age = 33.6 ± 9.2 years ; range = 20-51 years ) were referred to members of the French national sperm-banking network CECOS ; researchers analyzed medical history and sperm parameters , comparing TSC outcomes from baseline through six months of treatment . Normal sperm volume and values were considered ≥1.5 mL and ≥39 million / ejaculate , respectively .
After six months of treatment , mean TSC decreased from 129.815 million at
|
baseline to 24.1 ± 54.1 million . Median TSC dropped from 61.6 million ( range = 6.5-210 million ) at baseline to 0.63 million ( range = 0.0001-17 million ) at six months ( p < 0.0001 ), “ representing a strong reduction by approximately a factor of five ,” the authors reported .
Prior to treatment , 14 men ( 40 %) had abnormal TSC values , including one patient with cryptozoospermia ( defined as rare sperm cells ). After treatment ,
|
however , the number of men with abnormal TSC values increased to 30 patients ( 86 %; p > 0.0001 ). The number of men with cryptozoospermia also increased at six months to five patients ( 14 %). An additional six patients ( 17 %) became azoospermic ( defined as no sperm cells ). Of the 24 remaining patients , 19 were oligozoospermic ( low sperm concentration ), and only five displayed a normal TSC ( 14 %) at six months , |
compared with 21 men at baseline ( 60 %).
Hydroxyurea did not impact semen volume , the other parameter involved in the TSC ’ s determination , the authors reported ( 2.34 ± 1.66 mL at baseline vs . 2.50 ± 1.97 mL at 6 months ; p > 0.05 ).
Investigators also evaluated whether other SCA-related factors ( including transfusion volume , a clinical history of priapism , and vaso-occlusive crises [ VOC ] during study ) significantly
|
REVLIMID ® [ lenalidomide ] capsules , for oral use
Venous and Arterial Thromboembolism [ see Boxed Warning , Warnings and Precautions ( 5.4 )]
VTE and ATE are increased in patients treated with REVLIMID .
Deep vein thrombosis ( DVT ) was reported as a serious ( 7.4 %) or severe ( 8.2 %) adverse drug reaction at a higher rate in the REVLIMID / dexamethasone group compared to 3.1 % and 3.4 % in the placebo / dexamethasone group , respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups . In the NDMM study , DVT was reported as an adverse reaction ( all grades : 10.3 %, 7.2 %, 4.1 %), as a serious adverse reaction ( 3.6 %, 2.0 %, 1.7 %), and as a Grade 3 / 4 adverse reaction ( 5.6 %, 3.7 %, 2.8 %) in the Rd Continuous , Rd18 , and MPT Arms , respectively . Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms ( both < 1 %). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous ( 2.3 %) and Rd18 ( 1.5 %) arms . Pulmonary embolism ( PE ) was reported as a serious adverse drug reaction ( 3.7 %) or Grade 3 / 4 ( 4.0 %) at a higher rate in the REVLIMID / dexamethasone group compared to 0.9 % ( serious or grade 3 / 4 ) in the placebo / dexamethasone group in the 2 studies in patients with , at least 1 prior therapy , with discontinuations due to PE adverse reactions reported at comparable rates between groups . In the NDMM study , the frequency of adverse reactions of PE was similar between the Rd Continuous , Rd18 , and MPT Arms for adverse reactions ( all grades : 3.9 %, 3.3 %, and 4.3 %, respectively ), serious adverse reactions ( 3.8 %, 2.8 %, and 3.7 %, respectively ), and grade 3 / 4 adverse reactions ( 3.8 %, 3.0 %, and 3.7 %, respectively ).
Myocardial infarction was reported as a serious ( 1.7 %) or severe ( 1.7 %) adverse drug reaction at a higher rate in the REVLIMID / dexamethasone group compared to 0.6 % and 0.6 % respectively in the placebo / dexamethasone group . Discontinuation due to MI ( including acute ) adverse reactions was 0.8 % in REVLIMID / dexamethasone group and none in the placebo / dexamethasone group . In the NDMM study , myocardial infarction ( including acute ) was reported as an adverse reaction ( all grades : 2.4 %, 0.6 %, and 1.1 %), as a serious adverse reaction , ( 2.3 %, 0.6 %, and 1.1 %), or as a severe adverse reaction ( 1.9 %, 0.6 %, and 0.9 %) in the Rd Continuous , Rd18 , and MPT Arms , respectively .
Stroke ( CVA ) was reported as a serious ( 2.3 %) or severe ( 2.0 %) adverse drug reaction in the REVLIMID / dexamethasone group compared to 0.9 % and 0.9 % respectively in the placebo / dexamethasone group . Discontinuation due to stroke ( CVA ) was 1.4 % in REVLIMID / dexamethasone group and 0.3 % in the placebo / dexamethasone group . In the NDMM study , CVA was reported as an adverse reaction ( all grades : 0.8 %, 0.6 %, and 0.6 %), as a serious adverse reaction ( 0.8 %, 0.6 %, and 0.6 %), or as a severe adverse reaction ( 0.6 %, 0.6 %, 0.2 %) in the Rd Continuous , Rd18 , and MPT arms respectively .
6.2 Postmarketing Experience
The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID . 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 [ see Warnings and Precautions Section ( 5.7 to 5.10 , and 5.12 )] Skin and subcutaneous tissue disorders : Stevens-Johnson Syndrome , toxic epidermal necrolysis Immune system disorders : Angioedema , acute graft-versus-host disease ( following allogeneic hematopoietic transplant ) Neoplasms benign , malignant and unspecified ( incl cysts and polyps ): Tumor lysis syndrome , tumor flare reaction Respiratory , thoracic and mediastinal disorders : Pneumonitis Hepatobiliary disorders : Hepatic failure ( including fatality ), toxic hepatitis , cytolytic hepatitis , cholestatic hepatitis , mixed cytolytic / cholestatic hepatitis , transient abnormal liver laboratory tests Infections and infestations : Viral reactivation ( such as hepatitis B virus and herpes zoster ) Endocrine disorders : Hypothyroidism , hyperthyroidism
7 DRUG INTERACTIONS 7.1 Digoxin
When digoxin was co-administered with multiple doses of REVLIMID ( 10 mg / day ) the digoxin C max and AUC 0-∞ were increased by 14 %. Periodic monitoring of digoxin plasma levels , in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication , is recommended during administration of REVLIMID .
7.2 Concomitant Therapies That May Increase the Risk of Thrombosis
Erythropoietic agents , or other agents that may increase the risk of thrombosis , such as estrogen containing therapies , should be used with caution after making a benefit-risk assessment in patients receiving
REVLIMID [ see Warnings and Precautions ( 5.4 )].
7.3 Warfarin
Co-administration of multiple dose REVLIMID ( 10 mg ) with single dose warfarin ( 25 mg ) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin . Expected changes in laboratory assessments of PT and INR were observed after warfarin administration , but these changes were not affected by concomitant REVLIMID administration . It is not known whether there is an interaction between dexamethasone and warfarin . Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin .
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 REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID . This registry is also used to understand the root cause for the pregnancy . Report any suspected fetal exposure to REVLIMID 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 [ see
Data ], REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy [ see Boxed Warning , Contraindications ( 4.1 ), and Use in Specific Populations ( 5.1 )].
REVLIMID 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 .
Lenalidomide caused thalidomide-type limb defects in monkey offspring . Lenalidomide crossed the placenta after administration to pregnant rabbits and pregnant rats [ 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 REVLIMID 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
In an embryo-fetal developmental toxicity study in monkeys , teratogenicity , including thalidomide-like limb defects , occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis . Exposure ( AUC ) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose ( MRHD ) of 25 mg . Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively , produced embryo lethality in rabbits and no adverse reproductive effects in rats .
In a pre- and post-natal development study in rats , animals received lenalidomide from organogenesis through lactation . The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg / kg ( approximately 200 times the human dose of 25 mg based on body surface area ). The male offspring exhibited slightly delayed sexual maturation and the female offspring had