BEUDAMED
    FDA Adverse Event Injury Summary report: N

    RESTYLANE LIDOCAINE

    MDR report key: 17050445 · Received June 2, 2023

    Report

    Report Number
    9710154-2023-00037
    Event Type
    Injury
    Date Received
    June 2, 2023
    Report Date
    June 2, 2023
    Manufacturer
    Q-MED
    Product Code
    LMH
    PMA / PMN Number
    P040024/S039
    Adverse Event
    Yes
    Report Source
    Manufacturer report
    Reporter Location
    BR
    Reporter Occupation
    PHYSICIAN
    Health Professional
    Yes

    Narratives

    Additional Manufacturer Narrative · 0

    COMPANY COMMENT: THE SERIOUS EXPECTED EVENT OF INJECTION SITE ABSCESS STERILE AND THE NON-SERIOUS EXPECTED EVENTS OF ERYTHEMA, OEDEMA, PAIN AND INFLAMMATION AT IMPLANT SITE, AND PURULENT DISCHARGE WERE CONSIDERED POSSIBLY RELATED TO THE TREATMENT. SERIOUSNESS CRITERIA INCLUDE THE NEED FOR MEDICAL AND SURGICAL INTERVENTIONS TO PREVENT PERMANENT DAMAGE. THE POTENTIAL ROOT CAUSE IS THE TREATMENT PROCEDURE. THE CASE MEETS THE SERIOUSNESS CRITERIA FOR EXPEDITED REPORTING TO THE REGULATORY AUTHORITIES. EVALUATION TEXT:: RESTYLANE LIDOCAINE-ROUTINE INVESTIGATIONS HAVE BEEN PERFORMED AND PROVIDE SUFFICIENT INFORMATION TO ASSESS THE POTENTIAL ROOT CAUSE AND INDICATE A POSSIBLE ASSOCIATION TO THE TREATMENT PROCEDURE. LOT NUMBER WAS NOT REPORTED, AND THE PRODUCT COULD NOT BE VERIFIED. THE INFORMATION IN THIS CASE DOES NOT INDICATE A NON-CONFORMING PRODUCT OR MALFUNCTION. THE PERFORMED INVESTIGATIONS ARE THEREFORE CONSIDERED ADEQUATE, AND NO ADDITIONAL INVESTIGATIONS WILL BE CONDUCTED. CAPA COMMENT: NO CORRECTIVE OR PREVENTIVE ACTIONS ARE DEEMED NECESSARY BASED ON THE OUTCOME OF THE PERFORMED INVESTIGATIONS.

    Description of Event or Problem · 0

    CASE REFERENCE NUMBER: (B)(4) IS A LITERATURE REPORT IDENTIFIED ON 05-MAY-2023 DURING LITERATURE SEARCH. THIS CASE REFERS TO A 50-YEAR-OLD FEMALE PATIENT. THIS WAS CASE 1 OF 2 (SAME REPORTER). THIS CASE WAS IDENTIFIED FROM THE LITERATURE ARTICLE MUNHOZ G, CAVALLIERI FA, DE ALMEIDA BALASSIANO LK, TEMBRA MF, CUNHA JMT, SILVEIRA ACO ET AL. STERILE ABSCESS DUE TO HYALURONIC ACID: A NEW DIAGNOSIS AND A PROPOSAL FOR TREATMENT-A SERIES OF EIGHT CASES. J COSMET DERMATOL 2022;21(11):5562-5568. INTRODUCTION: IN THIS STUDY, WE DESCRIBE AN ADVERSE REACTION AFTER FILLING WITH HA PRESENTING CLINICAL, LABORATORY, AND ULTRASOUND SIMILARITIES IN EIGHT PATIENTS. THE COMPLICATION WAS NOT INITIALLY RESPONSIVE TO THE TREATMENTS PREVIOUSLY RECOMMENDED IN THE LITERATURE. HOWEVER, ALL CASES EVOLVED WITH COMPLETE RESOLUTION AFTER THE PROTOCOL DEVELOPED BY THE AUTHORS NAMED MUNHOZ-CAVALLIERI LAVAGE PROTOCOL. MATERIALS AND METHODS: WE REPORT A SERIES OF EIGHT CASES OF FACIAL ABSCESSES AFTER INJECTIONS OF HA EVALUATED AND FOLLOWED UP BY THE AUTHORS. DIAGNOSTIC EVALUATION - FACE ULTRASOUND: ALL EIGHT CASES HAD FACIAL ULTRASONOGRAPHY FOR DIAGNOSTIC EVALUATION AND INTERVENTION GUIDANCE (DRAINAGE OF THE MATERIAL AND INJECTION OF THE SOLUTION CREATED BY THE AUTHORS, CALLED MUNHOZ-CAVALLIERI LAVAGE PROTOCOL). ULTRASOUND IMAGES WERE OBTAINED WITH EPIQ7 EQUIPMENT (PHILIPS MEDICAL SYSTEMS, BOTHELL, WA, USA), AND TWO HIGH-FREQUENCY TRANSDUCERS (7 TO 15 AND 4 TO 18 [?]MHZ) WERE USED. ULTRASOUND EXAMINATION INCLUDED A B-MODE ASSESSMENT ASSOCIATED WITH COLOR DOPPLER TO EVALUATE LOCAL VASCULARIZATION. A LARGE VOLUME OF GEL WAS USED BETWEEN THE TRANSDUCER AND THE REGION, AND THE LEAST POSSIBLE COMPRESSION WITH THE TRANSDUCER, TO OBTAIN THE BEST ACCURACY OF SUPERFICIAL STRUCTURES. THE PATIENTS WERE INITIALLY SUBMITTED TO AN ULTRASOUND EXAMINATION, ALWAYS PERFORMED OR MONITORED REMOTELY BY THE SAME RADIOLOGIST, ONE OF THE AUTHORS OF THIS ARTICLE, AIMING TO IDENTIFY THE FILLER MATERIAL USED, EXCLUDE A FILLER OTHER THAN HA, AND ASSESS THE PRESENCE AND CHARACTERISTICS OF THE COLLECTION. ULTRASOUND DIAGNOSIS OF THE COLLECTION WAS PERFORMED IN THE PRESENCE OF AN ANECHOIC WELL-DEFINED IMAGE, WHICH MAY HAVE SUSPENDED DEBRIS AND BECOME ISOECHOIC, ACCORDING TO THE HIGH PROTEIN CONTENT OF THE COLLECTION (THE HIGHER THE PROTEIN CONTENT, THE MORE ISOECHOIC). DURING DYNAMIC COMPRESSION AND EVALUATION, IT WAS POSSIBLE TO VISUALIZE THE FLUID IN THE COLLECTION. IN THE COLOR DOPPLER ANALYSIS, PERIPHERAL VASCULARIZATION OF THE COLLECTION STOOD OUT, AND NEVER INSIDE THE IMAGE. IN SOME CASES, SIGNS OF PANNICULITIS OF THE SURROUNDING SUBCUTANEOUS TISSUE WERE OBSERVED. THE COLLECTIONS WERE LOCATED AT THE LAYER WHERE HA WAS INJECTED: SUBCUTANEOUS, INTRAMUSCULAR, OR PERIOSTEAL COLLECTIONS WERE OBSERVED. LABORATORY EXAMINATIONS: ALL PATIENTS HAD LABORATORY BLOOD TESTS, INCLUDING WHITE BLOOD CELL COUNT AND INFLAMMATORY FUNCTION TESTS (CRP AND ESR). BLOODWORK PRESENTED RESULTS SHOWING AN INFLAMMATORY CONDITION, AND FOUR PATIENTS HAD MILD LEUKOCYTOSIS; THREE HAD INCREASED ESR, THREE HAD ELEVATED CRP, AND ONLY ONE PATIENT HAD NO ABNORMALITIES IN LABORATORY TESTS. ANALYSIS OF THE DRAINED MATERIAL: DUE TO THE PRESENCE OF THE COLLECTION, US-GUIDED DRAINAGE WAS PERFORMED, WITH THE WITHDRAWAL OF THICK LIQUID MATERIAL, RANGING FROM PURULENT, SEROPURULENT, AND SEROSANGUINEOUS. MOST PATIENTS WERE NOT USING ANTIBIOTICS AND/OR ORAL CORTICOSTEROIDS AT THE TIME OF THE DRAINAGE. CONSIDERING THAT THE PRE-ANALYTICAL PROCESS IS OF GREAT IMPORTANCE FOR A RELIABLE RESULT, THE MATERIAL WAS COLLECTED USING A STRICT ASEPSIS AND ANTISEPSIS PROTOCOL RECOMMENDED BY THE MICROBIOLOGIST. THE CONTENT WAS THEN SENT IMMEDIATELY FOR ANALYSIS IN A MICROBIOLOGY LABORATORY. THE ASPIRATED MATERIAL WAS DIVIDED INTO THREE STERILE FLASKS, AND THE FOLLOWING TESTS WERE REQUESTED: FLASK 01: CYTOLOGY, FLASK 02: SEARCH FOR COMMON GERMS (GRAM AND CULTURE), AND FLASK 03: RESEARCH FOR MYCOBACTERIA (CULTURE, PCR AND ZIEHLNEELSEN). THERE WAS NO GROWTH OF MICROORGANISMS IN ANY CASE, AND THEREFORE THE AUTHORS PROPOSED THE TERM STERILE ABSCESS FOR THIS SPECIFIC COMPLICATION. MUNHOZ-CAVALLIERI LAVAGE PROTOCOL: AFTER COLLECTION DRAINAGE, THE PATIENT WAS SUBMITTED TO THE LAVAGE PROTOCOL, PROPOSED BY THE AUTHORS. THE MUNHOZ-CAVALLIERI LAVAGE PROTOCOL CONSISTS OF THE FOLLOWING: 1. ANESTHETIC BUTTON WITH LIDOCAINE FOR THE NEEDLE ENTRY HOLE. 2. ASPIRATION OF MATERIAL FOR MICROBIOLOGICAL STUDY-(INCLUDING THE TWO PATIENTS THAT WERE ON ANTIBIOTIC THERAPY). 3. SOLUTION FOR LAVAGE PROTOCOL: HYALURONIDASE REDUCTONIDASA DILUTED WITH 3 ML OF STERILE SALINE SOLUTION (1500 [?]IU) [?]+ 3 ML OF STERILE SALINE[?]+ 1 ML TRIAMCINOLONE 20 [?]MG/ML[?]+ 3 ML OF 2% LIDOCAINE FOR A TOTAL OF 10 ML OF SOLUTION. 4. CARRYING OUT THE WASHING WITH A 3 ML SYRINGE AND A 22G OR 23G NEEDLE: INJECTION OF 1-3 ML OF THE SOLUTION, ASPIRATING, AND DISPOSING. THE PROCESS IS REPEATED TWO TO THREE TIMES TO WASH THE COLLECTION AREA. DISCARD THE SYRINGES AND NEEDLES USED IN EACH STEP. 5. DURING THE THIRD OR FOURTH INJECTION, WITH STERILE SYRINGE AND NEEDLES, IT WAS DEPOSITED 0.5-3 ML OF THE SOLUTION INTO THE CAVITY, TO OCCUPY THE PURULENT SECRETION SPACE, THAT IS, TO COLLAPSE THE SPACE VISUALIZED ON THE US AND DILUTE THE REMAINING HA. AFTER THE LAVAGE PROTOCOL, ALL PATIENTS REACHED CURE CRITERIA, INCLUDING CLINICAL, LABORATORY, AND ULTRASONOGRAPHIC IMPROVEMENT. IT WAS NOT NECESSARY TO KEEP MEDICATIONS OR ANTIBIOTICS DURING OR AFTER THE PROTOCOL. RESULTS: THE EIGHT CASES OCCURRED IN WOMEN AGED BETWEEN 26 AND 71 [?]YEARS. A COMMON FEATURE IS THE CLINICAL HISTORY OF UNILATERAL FACIAL EDEMA ASSOCIATED WITH FEW ERYTHEMA, WARM, AND PAIN IN SITES PREVIOUSLY TREATED WITH INJECTABLE HA. TWO PATIENTS COMPLAINED OF TRISMUS. NONE HAD A FEVER. TWO PATIENTS ONLY MANIFESTED INTENSE EDEMA WITHOUT PHLOGISTIC SIGNS. SIX OF THE EIGHT CASES HAD A RECENT ONSET WITHIN 30 [?]DAYS AFTER HA INJECTION, AND TWO WERE LATE, WITH ONSET AFTER 30 [?]DAYS OF APPLYING THE FILLER. THE FOLLOWING PRODUCTS HAVE BEEN IDENTIFIED: RESTYLANE DEFYNE (GALDERMA/Q-MED, SWEDEN), HIALUROX (LABORATÓRIO TERMOFRIO, SP, BRASIL), JUVEDERM VOLUX (ALLERGAN, INC., IRVINE, CA, USA), AND JUVEDERM VOLUMA (ALLERGAN, INC.). ALL CASES RESPONDED PARTIALLY TO DIFFERENT PROTOCOLS OF ORAL ANTIBIOTICS AND ORAL CORTICOSTEROIDS, RECURRING AT VARIABLE INTERVALS AFTER DISCONTINUING THE MEDICATIONS. THE NUMBER OF ANTIBIOTICS USED RANGED FROM 01 TO 09 PER PATIENT. ALL PATIENTS HAD SOFT TISSUE ULTRASONOGRAPHY WITH A DIAGNOSIS OF THICK FLUID COLLECTION CORRESPONDING TO THE SWOLLEN AREA AT THE SITE OF THE PREVIOUS HA INJECTION. ULTRASOUND IMAGES OF THE CONTRALATERAL SIDE OF THE FACE SHOWED THE PRESENCE OF FOCAL HA DEPOSITS. FOUR PATIENTS WERE SUBMITTED TO BLIND APPLICATION OF HYALURONIDASE TO DILUTE THE HA WITH LITTLE RESPONSE. THREE HAD ULTRASOUND GUIDED DRAINAGE WITH A DISCHARGE OF PURULENT MATERIAL, WITH A RECURRENCE OF THE COLLECTION. MOST PATIENTS UNDERWENT MORE THAN ONE DRAINAGE WITHOUT SUCCESS. ONE PATIENT HAD NO OTHER TREATMENT BESIDES THE LAVAGE PROTOCOL, AT A LATER MOMENT. TWO PATIENTS PRESENTED RECURRENT ABSCESSES ON THE CONTRALATERAL SIDE OF THE FACE, 4[?]WEEKS AFTER THE LAVAGE PROTOCOL, IN SITES OF PREVIOUS INJECTION WITH HYALURONIC ACID AND NOT TREATED BEFORE. BOTH CASES WERE TREATED WITH A SINGLE MUNHOZ-CAVALLIERI LAVAGE PROTOCOL PROCEDURE WITH FULL RESOLUTION. GIVEN THE CLINICAL HISTORIES THAT INCLUDED EPISODES OF RELAPSES, MULTIPLE INCOMPLETE REGIMENS OF ORAL ANTIBIOTICS AND PREVIOUS UNSUCCESSFUL DRAINAGES, THE AUTHORS ESTABLISHED A FLOWCHART FOR MANAGING THESE CASES, AS DESCRIBED ABOVE AS MUNHOZ-CAVALLIERI LAVAGE PROTOCOL. ALL PATIENTS REMAIN FREE OF RECURRENT EPISODES AFTER 1.5[?]YEARS OF AVERAGE FOLLOW-UP. CASE REPORT: A 50-YEAR-OLD FEMALE PATIENT WAS TREATED WITH 1ML OF RESTYLANE LIDOCAINE, 0.5 ML TO EACH SIDE OF TEAR TROUGH USING A CANNULA. FIVE DAYS AFTER TREATMENT, THE PATIENT EXPERIENCED FEW ERYTHEMA, EDEMA AND PAIN ON THE LEFT TEAR TROUGH AREA. NO TRIGGER FACTORS WERE IDENTIFIED. LABORATORY EXAMINATION REVEALED LEUKOCYTOSIS, INCREASED ESR AND NORMAL CRP. BLOODWORK RESULTS SHOWING AN INFLAMMATORY CONDITION. ULTRASOUND EXAMINATION REVEALED THICK FLUID COLLECTION CORRESPONDING TO THE SWOLLEN AREA AT THE SITE OF THE PREVIOUS HA INJECTION. MICROBIOLOGY ANALYSIS WAS STERILE. BEFORE CLEANING PROTOCOL, THE PATIENT WAS TREATED WITH 3 ANTIBIOTICS, ORAL CORTICOID AND ONCE WITH HYALURONIDASE. THEREAFTER, THE PATIENT WAS TREATED WITH MUNHOZ-CAVALLIERI LAVAGE PROTOCOL TWICE AND THE PATIENT REACHED THE CURE CRITERIA INCLUDING CLINICAL, LABORATORY, AND ULTRASONOGRAPHIC IMPROVEMENT. IT WAS NOT NECESSARY TO KEEP MEDICATIONS OR ANTIBIOTICS DURING OR AFTER THE PROTOCOL. DISCUSSION: IN THIS ARTICLE, THE AUTHORS REPORT EIGHT CASES OF A COMPLICATION STILL VERY LITTLE KNOWN: THE STERILE ABSCESS AFTER HA INJECTION. IN LITERATURE, WE COULD FIND ONLY ONE CASE DESCRIBED AFTER USING HA AS FILLER. FACED WITH A PATIENT PRESENTING UNILATERAL OR BILATERAL EDEMA WITH FEW PHLOGISTIC SIGNS IN A SITE PREVIOUSLY TREATED WITH INJECTABLE HA, THE PROCEDURE PROPOSED BY THE AUTHORS INITIALLY CONSISTS OF PERFORMING AN ULTRASOUND EXAM TO ASSESS THE PRESENCE OR ABSENCE OF A COLLECTION. WITH THE POSSIBILITY OF DYNAMIC VISUALIZATION OF FLUID COLLECTION AND ESTIMATE OF ITS TOTAL VOLUME AND LOCATION, IT IS POSSIBLE TO ASPIRATE THE MATERIAL FOR MICROBIOLOGICAL STUDY AND GUIDE THE MUNHOZ - CAVALLIERI LAVAGE PROTOCOL. THE IMAGING METHOD ALLOWS THE VISUALIZATION OF THE BEST SITE FOR PUNCTURE, AND THE ASSESSMENT OF THE RESOLUTION, WHICH IS THE COMPLETE EMPTYING THE COLLECTION. THE DRAINED MATERIAL MUST BE SENT FOR ANALYSIS TO A SPECIFIC MICROBIOLOGY LABORATORY IMMEDIATELY AFTER DRAINAGE AND MUST NOT BE STORED IN A REFRIGERATOR. ABOUT 70%-80% OF THE MATERIALS ARE DISCARDED DUE TO THE PRE-ANALYTICAL DIFFICULTY, WHICH IS WHY WE ESTABLISHED A STRICT PROTOCOL OF ASEPSIS, ANTISEPSIS, AND STORAGE IN A STERILE FLASK. THEN, THE THREE SAMPLES SHOULD BE SENT TO LABORATORY STUDY, ONE FOR CYTOLOGY, ONE FOR THE RESEARCH OF COMMON GERMS (CULTURE, GRAM, AND BACTERIAL PCR), AND A SAMPLE FOR SCREENING FOR MYCOBACTERIA (CULTURE, PCR AND ZIEHLNEELSEN). IN THE EVENT OF NOT FINDING THE BACTERIA AND/OR MYCOBACTERIA IN THE GRAM AND NOT GROWING IN ADEQUATE CULTURE MEDIA, CLASSIFIES THE PURULENT COLLECTION AS A STERILE ABSCESS. THUS, WE EMPHASIZE THAT NOT EVERY PURULENT COLLECTION IS SYNONYMOUS WITH INFECTION. PUS MAY BE JUST THE RESULT OF PUTREFACTION OF INFLAMMATORY CELLS. THE PATHOGENESIS OF HA-INDUCED STERILE ABSCESSES IS NOT ENTIRELY CLEAR. THE IMMUNOGENIC CHARACTERISTIC OF EACH ANATOMICAL LAYER, THE RELATION BETWEEN TISSUE LAYER AND THE TECHNIQUE, IN ADDITION TO THE RHEOLOGY AND THE PROPERTIES OF THE PRODUCT ARE FACTORS TO BE CONSIDERED IN THE PATHOPHYSIOLOGY OF COMPLICATIONS. HA INTERACTS WITH SEVERAL RECEPTORS ON ENDOTHELIAL CELLS AND PHAGOCYTES, PARTICIPATING IN BOTH INFLAMMATORY PROCESSES AND TISSUE REPAIR. THE TRAUMA RELATED TO THE PROCEDURE, THE CONCOMITANT SYSTEMIC INFECTION, AND THE PARTIAL DEGRADATION OF THE INJECTED PRODUCT CAN CONTRIBUTE TO THE TRIGGERING OF STERILE INFLAMMATION, FROM THE ENGAGEMENT OF CELLS AND RECEPTORS OF INNATE IMMUNITY, CAPABLE OF RECOGNIZING HARMFUL SIGNALS FOR CELLS AND TISSUES IN THE ABSENCE OF INFECTION. THE STRATEGY OF COMBINING HYALURONIDASE WITH INTRALESIONAL CORTICOSTEROID THERAPY BROUGHT A FAVORABLE OUTCOME IN THE EIGHT CASES ANALYZED BY ELIMINATING THE TRIGGER (INTACT FILLER AND ITS DEGRADATION PRODUCTS) AND LOCALLY INHIBITING THE INFLAMMATORY CELLS. SOME AUTHORS QUESTION THE ROLE OF BACTERIAL BIOFILMS - COMMUNITIES OF UNICELLULAR ORGANISMS ATTACHED TO A SURFACE THROUGH A POLYSACCHARIDE MATRIX-IN THE PATHOGENESIS OF LATE COMPLICATIONS OF INJECTABLE FILLERS. STERILE ABSCESS AFTER INJECTABLE HA MAY ALSO OCCUR EVEN LONG AFTER THE PRODUCT WAS INJECTED. IN BOTH SITUATIONS, STERILE ABSCESS OR PRESENCE OF A BIOFILM IN THE DRAINED MATERIAL COULD RESULT IN NEGATIVE CULTURE, BECAUSE THE BACTERIA IN BIOFILMS GROW COVERED BY A POLYSACCHARIDE LAYER, WHICH AVOIDS THE DETECTION OF THE MICROORGANISM UNDERNEATH IT. HOWEVER, IN FACE OF BIOFILMS, TREATMENT SHOULD INCLUDE REMOVAL OF INFECTED INDWELLING DEVICES AND SELECTION OF WELL PENETRATING AND SENSITIVE ANTIBIOTICS. NEVERTHELESS, FOR ALL THE PATIENTS IN OUR CASE SERIES, THE CURE WAS REACHED WITHOUT THE USE OF ANTIBIOTICS. THEREFORE, WE BELIEVE THAT THE INFLAMMATORY REACTION OBSERVED IN THIS CASE SERIES IS AN EXACERBATED FOREIGN BODY IMMUNOGENIC REACTION TO HA, WITHOUT THE OBLIGATORY PRESENCE OF BACTERIA. HOWEVER, THIS IS A DIFFICULT HYPOTHESIS TO REFUTE, CONSIDERING THE DIFFICULTY IN ITS DIAGNOSIS, AND MORE STUDIES ARE NECESSARY TO REACH ACCURATE INFORMATION. THE MUNHOZ-CAVALLIERI LAVAGE PROTOCOL (WASHING THE CAVITY, WITH AN ASSOCIATION OF HYALURONIDASE, STERILE SALINE SOLUTION, AND INJECTABLE CORTICOSTEROID) WAS CREATED AFTER SEVERAL ATTEMPTS TO TREAT SITES PREVIOUSLY FILLED WITH HA USING ANTIBIOTICS AND ORAL CORTICOSTEROIDS, HYALURONIDASE, AND EVEN AFTER ULTRASOUND-GUIDED DRAINAGE, WITH NO SUCCESS FOR RECURRENT ABSCESSES. CONCLUSION: STERILE ABSCESSES IS A LITTLE-KNOWN CONDITION AMONG COMPLICATIONS AFTER FILLING WITH HÁ THAT WAS PREVIOUSLY TREATED AS INFECTIOUS ABSCESSES WITHOUT SUCCESS. POSSIBLE ETIOLOGY INCLUDES IMMUNOGENICITY OF HA PRESENT IN THE TISSUE SETTING OF AN INFLAMMATORY OVERREACTION. MUNHOZ-CAVALLIERI LAVAGE PROTOCOL SERVES AS A GUIDELINE IN DIAGNOSIS AND MANAGEMENT OF THIS CONDITION.

    Devices

    Seq Brand Generic Product Code Manufacturer Model Lot UDI-DI
    1371134 RESTYLANE LIDOCAINE IMPLANT, DERMAL, FOR AESTHETIC USE LMH Q-MED

    Patients

    Seq Age Sex Outcome Treatment
    1 50 YR Female Required Intervention