INDICATIONS
AVEED IS INDICATED FOR TESTOSTERONE REPLACEMENT THERAPY IN ADULT MALES FOR CONDITIONS ASSOCIATED WITH A DEFICIENCY OR ABSENCE OF ENDOGENOUS TESTOSTERONE.
" PRIMARY HYPOGONADISM (CONGENITAL OR ACQUIRED): TESTICULAR FAILURE DUE TO CRYPTORCHIDISM, BILATERAL TORSION, ORCHITIS, VANISHING TESTIS SYNDROME, ORCHIECTOMY, KLINEFELTER'S SYNDROME, CHEMOTHERAPY, OR TOXIC DAMAGE FROM ALCOHOL OR HEAVY METALS. THESE MEN USUALLY HAVE LOW SERUM TESTOSTERONE CONCENTRATIONS AND GONADOTROPINS (FOLLICLE-STIMULATING HORMONE [FSH], LUTEINIZING HORMONE [LH]) ABOVE THE NORMAL RANGE.
" HYPOGONADOTROPIC HYPOGONADISM (CONGENITAL OR ACQUIRED): IDIOPATHIC GONADOTROPIN OR LUTEINIZING HORMONE-RELEASING HORMONE (LHRH) DEFICIENCY OR PITUITARY-HYPOTHALAMIC INJURY FROM TUMORS, TRAUMA, OR RADIATION. THESE MEN HAVE LOW TESTOSTERONE SERUM CONCENTRATIONS BUT HAVE GONADOTROPINS IN THE NORMAL OR LOW RANGE.
AVEED SHOULD ONLY BE USED IN PATIENTS WHO REQUIRE TESTOSTERONE REPLACEMENT THERAPY AND IN WHOM THE BENEFITS OF THE PRODUCT OUTWEIGH THE SERIOUS RISKS OF PULMONARY OIL MICROEMBOLISM AND ANAPHYLAXIS.
LIMITATIONS OF USE
" SAFETY AND EFFICACY OF AVEED IN MALES LESS THAN 18 YEARS OLD HAVE NOT BEEN ESTABLISHED [SEE USE IN SPECIFIC POPULATIONS].
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
750 MG/3 ML (250 MG/ML) TESTOSTERONE UNDECANOATE STERILE INJECTABLE SOLUTION IS PROVIDED IN AN AMBER GLASS, SINGLE USE VIAL WITH SILVER-COLORED CRIMP SEAL AND GRAY PLASTIC CAP.
STORAGE AND HANDLING
AVEED, NDC 67979-511-43: 750 MG/3 ML (250 MG/ML) TESTOSTERONE UNDECANOATE STERILE INJECTABLE SOLUTION IS PROVIDED IN AN AMBER GLASS VIAL WITH SILVER-COLORED CRIMP SEAL AND GRAY PLASTIC CAP. EACH VIAL IS INDIVIDUALLY PACKAGED IN A CARTON BOX.
STORE AT CONTROLLED ROOM TEMPERATURE 25 °C (77 °F); EXCURSIONS PERMITTED TO 15 -30 °C (59 -86 °F) [SEE USP CONTROLLED ROOM TEMPERATURE] IN ITS ORIGINAL CARTON UNTIL THE DATE INDICATED.
BEFORE USE, EACH VIAL SHOULD BE VISUALLY INSPECTED. ONLY VIALS FREE FROM PARTICLES SHOULD BE USED.
SINGLE USE VIAL. DISCARD UNUSED PORTION.
MANUFACTURED FOR: ENDO PHARMACEUTICALS SOLUTIONS INC. MALVERN, PA 19355. REVISED: MARCH 2015
DOSAGE AND ADMINISTRATION
DOSAGE
AVEED IS FOR INTRAMUSCULAR USE ONLY. DOSAGE TITRATION IS NOT NECESSARY.
INJECT AVEED DEEPLY INTO THE GLUTEAL MUSCLE FOLLOWING THE USUAL PRECAUTIONS FOR INTRAMUSCULAR ADMINISTRATION; CARE MUST BE TAKEN TO AVOID INTRAVASCULAR INJECTION [SEE ADMINISTRATION INSTRUCTIONS BELOW]. INTRAVASCULAR INJECTION OF AVEED MAY LEAD TO PULMONARY OIL MICROEMBOLISM [SEE WARNINGS AND PRECAUTIONS].
THE RECOMMENDED DOSE OF AVEED IS 3 ML (750 MG) INJECTED INTRAMUSCULARLY, FOLLOWED BY 3 ML (750 MG) INJECTED AFTER 4 WEEKS, THEN 3 ML (750 MG) INJECTED EVERY 10 WEEKS THEREAFTER.
PREPARATION INSTRUCTIONS
PARENTERAL DRUG PRODUCTS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION, WHENEVER SOLUTION AND CONTAINER PERMIT.
CAREFULLY REMOVE THE GRAY PLASTIC CAP FROM THE TOP OF THE VIAL BY LIFTING IT UP FROM THE EDGES WITH YOUR FINGERS OR BY PUSHING THE BOTTOM EDGE OF THE CAP UPWARD USING THE TOP OF YOUR THUMB. REMOVE ONLY THE GRAY PLASTIC CAP WHILE LEAVING THE ALUMINUM METAL RING AND CRIMP SEAL AROUND THE GRAY RUBBER STOPPER IN PLACE. TO FACILITATE THE REMOVAL OF MEDICATION FROM THE VIAL, YOU CAN DRAW 3 ML OF AIR INTO THE SYRINGE AND INJECT IT THROUGH THE GRAY RUBBER STOPPER INTO THE VIAL TO CREATE POSITIVE PRESSURE WITHIN THE VIAL CHAMBER.
WITHDRAW 3 ML (750 MG) OF AVEED SOLUTION FROM THE VIAL. EXPEL EXCESS AIR BUBBLES FROM THE SYRINGE. REPLACE THE SYRINGE NEEDLE USED TO DRAW UP THE SOLUTION FROM THE VIAL WITH A NEW INTRAMUSCULAR NEEDLE AND INJECT. DISCARD ANY UNUSED PORTION IN THE VIAL.
ADMINISTRATION INSTRUCTIONS
THE SITE FOR INJECTION FOR AVEED IS THE GLUTEUS MEDIUS MUSCLE SITE LOCATED IN THE UPPER OUTER QUADRANT OF THE BUTTOCK. CARE MUST BE TAKEN TO AVOID THE NEEDLE HITTING THE SUPERIOR GLUTEAL ARTERIES AND SCIATIC NERVE. BETWEEN CONSECUTIVE INJECTIONS, ALTERNATE THE INJECTION SITE BETWEEN LEFT AND RIGHT BUTTOCK.
FIGURE 2: IDENTIFYING THE INJECTION SITE
FOLLOWING ANTISEPTIC SKIN PREPARATION, ENTER THE MUSCLE AND MAINTAIN THE SYRINGE AT A 90° ANGLE WITH THE NEEDLE IN ITS DEEPLY IMBEDDED POSITION. GRASP THE BARREL OF THE SYRINGE FIRMLY WITH ONE HAND. WITH THE OTHER HAND, PULL BACK ON THE PLUNGER AND ASPIRATE FOR SEVERAL SECONDS TO ENSURE THAT NO BLOOD APPEARS. IF ANY BLOOD IS DRAWN INTO THE SYRINGE, IMMEDIATELY WITHDRAW AND DISCARD THE SYRINGE AND PREPARE ANOTHER DOSE.
IF NO BLOOD IS ASPIRATED, REINFORCE THE CURRENT NEEDLE POSITION TO AVOID ANY MOVEMENT OF THE NEEDLE AND SLOWLY (OVER 60 TO 90 SECONDS) DEPRESS THE PLUNGER CAREFULLY AND AT A CONSTANT RATE, UNTIL ALL THE MEDICATION HAS BEEN DELIVERED. BE SURE TO DEPRESS THE PLUNGER COMPLETELY WITH SUFFICIENT CONTROLLED FORCE. WITHDRAW THE NEEDLE.
IMMEDIATELY UPON REMOVAL OF THE NEEDLE FROM THE MUSCLE, APPLY GENTLE PRESSURE WITH A STERILE PAD TO THE INJECTION SITE. IF THERE IS BLEEDING AT THE SITE OF INJECTION, APPLY A BANDAGE.
FOLLOWING EACH INJECTION OF AVEED, OBSERVE PATIENTS IN THE HEALTHCARE SETTING FOR 30 MINUTES IN ORDER TO PROVIDE APPROPRIATE MEDICAL TREATMENT IN THE EVENT OF SERIOUS POME REACTIONS OR ANAPHYLAXIS (SEE WARNINGS AND PRECAUTIONS).
SIDE EFFECTS
CLINICAL TRIAL EXPERIENCE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN CLINICAL PRACTICE.
AVEED WAS EVALUATED IN AN 84-WEEK CLINICAL STUDY USING A DOSE REGIMEN OF 750 MG (3 ML) AT INITIATION, AT 4 WEEKS, AND EVERY 10 WEEKS THEREAFTER IN 153 HYPOGONADAL MEN. THE MOST COMMONLY REPORTED ADVERSE REACTIONS ( > 2%) WERE: ACNE (5.2%), INJECTION SITE PAIN (4.6%), PROSTATE SPECIFIC ANTIGEN INCREASED (4.6%), HYPOGONADISM (2.6%) AND ESTRADIOL INCREASED (2.6%).
TABLE 1 PRESENTS ADVERSE REACTIONS REPORTED BY ? 1% OF PATIENTS IN THE 84-WEEK CLINICAL STUDY.
TABLE 1 : ADVERSE REACTIONS REPORTED IN AT LEAST 1% OF PATIENTS IN THE 84-WEEK CLINICAL STUDY OF AVEED
MEDDRA PREFERRED TERM NUMBER OF PATIENTS (%)
AVEED 750 MG
(N=153)
ACNE 8 (5.2%)
INJECTION SITE PAIN 7 (4.6%)
PROSTATIC SPECIFIC ANTIGEN INCREASED* 7 (4.6%)
ESTRADIOL INCREASED 4 (2.6%)
HYPOGONADISM 4 (2.6%)
FATIGUE 3 (2%)
IRRITABILITY 3 (2%)
HEMOGLOBIN INCREASED 3 (2%)
INSOMNIA 3 (2%)
MOOD SWINGS 3 (2%)
AGGRESSION 2 (1.3%)
EJACULATION DISORDER 2 (1.3%)
INJECTION SITE ERYTHEMA 2 (1.3%)
HEMATOCRIT INCREASED 2 (1.3%)
HYPERHIDROSIS 2 (1.3%)
PROSTATE CANCER 2 (1.3%)
PROSTATE INDURATION 2 (1.3%)
WEIGHT INCREASED 2 (1.3%)
*PROSTATE SPECIFIC ANTIGEN INCREASED DEFINED AS A SERUM PSA CONCENTRATION > 4 NG/ML.
IN THE 84-WEEK CLINICAL TRIAL, 7 PATIENTS (4.6%) DISCONTINUED TREATMENT BECAUSE OF ADVERSE REACTIONS. ADVERSE REACTIONS LEADING TO DISCONTINUATION INCLUDED: HEMATOCRIT INCREASED, ESTRADIOL INCREASED, PROSTATIC SPECIFIC ANTIGEN INCREASED, PROSTATE CANCER, MOOD SWINGS, PROSTATIC DYSPLASIA, ACNE, AND DEEP VEIN THROMBOSIS.
DURING THE 84-WEEK CLINICAL TRIAL, THE AVERAGE SERUM PSA INCREASED FROM 1.0 ± 0.8 NG/ML AT BASELINE TO 1.5 ±1.3 NG/ML AT THE END OF STUDY. FOURTEEN PATIENTS (10.9%) IN WHOM THE BASELINE PSA WAS < 4 NG/ML HAD A POST-BASELINE SERUM PSA OF > 4 NG/ML DURING THE 84-WEEK TREATMENT PERIOD.
A TOTAL OF 725 HYPOGONADAL MEN RECEIVED INTRAMUSCULAR TESTOSTERONE UNDECANOATE IN A TOTAL OF 7 CONTROLLED CLINICAL TRIALS. IN THESE CLINICAL TRIALS, THE DOSE AND DOSE FREQUENCY OF INTRAMUSCULAR TESTOSTERONE UNDECANOATE VARIED FROM 750 MG TO 1000 MG, AND FROM EVERY 9 WEEKS TO EVERY 14 WEEKS. SEVERAL OF THESE CLINICAL TRIALS INCORPORATED ADDITIONAL DOSES UPON INITIATION OF THERAPY (E.G., LOADING DOSES). IN ADDITION TO THOSE ADVERSE REACTIONS NOTED IN TABLE 1, THE FOLLOWING ADVERSE EVENTS WERE REPORTED BY AT LEAST 3% OF PATIENTS IN THESE TRIALS, IRRESPECTIVE OF THE INVESTIGATOR'S ASSESSMENT OF RELATIONSHIP TO STUDY MEDICATION: SINUSITIS, PROSTATITIS, ARTHRALGIA, NASOPHARYNGITIS, UPPER RESPIRATORY TRACT INFECTION, BRONCHITIS, BACK PAIN, HYPERTENSION, DIARRHEA AND HEADACHE.
PULMONARY OIL MICROEMBOLISM (POME) AND ANAPHYLAXIS IN CONTROLLED CLINICAL STUDIES
ADVERSE EVENTS ATTRIBUTABLE TO PULMONARY OIL MICROEMBOLISM AND ANAPHYLAXIS WERE REPORTED IN A SMALL NUMBER OF PATIENTS IN CONTROLLED CLINICAL TRIALS. IN THE 84-WEEK CLINICAL TRIAL OF AVEED, 1 PATIENT EXPERIENCED A MILD COUGHING FIT LASTING 10 MINUTES AFTER HIS THIRD INJECTION, WHICH WAS RETROSPECTIVELY ATTRIBUTED TO POME. IN ANOTHER CLINICAL TRIAL OF INTRAMUSCULAR TESTOSTERONE UNDECANOATE (1000 MG), A HYPOGONADAL MALE PATIENT EXPERIENCED THE URGE TO COUGH AND RESPIRATORY DISTRESS AT 1 MINUTE AFTER HIS TENTH INJECTION, WHICH WAS ALSO RETROSPECTIVELY ATTRIBUTED TO POME.
DURING A REVIEW THAT INVOLVED ADJUDICATION OF ALL CASES MEETING SPECIFIC CRITERIA, 9 POME EVENTS IN 8 PATIENTS AND 2 EVENTS OF ANAPHYLAXIS AMONG 3,556 PATIENTS TREATED WITH INTRAMUSCULAR TESTOSTERONE UNDECANOATE IN 18 CLINICAL TRIALS WERE JUDGED TO HAVE OCCURRED.
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POST-APPROVAL USE OF AVEED. BECAUSE THE 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.
PULMONARY OIL MICROEMBOLISM (POME) AND ANAPHYLAXIS
SERIOUS PULMONARY OIL MICROEMBOLISM (POME) REACTIONS, INVOLVING COUGH, URGE TO COUGH, DYSPNEA, HYPERHIDROSIS, THROAT TIGHTENING, CHEST PAIN, DIZZINESS, AND SYNCOPE, HAVE BEEN REPORTED TO OCCUR DURING OR IMMEDIATELY AFTER THE INJECTION OF INTRAMUSCULAR TESTOSTERONE UNDECANOATE 1000 MG (4 ML) IN POST-APPROVAL USE OUTSIDE THE UNITED STATES. THE MAJORITY OF THESE EVENTS LASTED A FEW MINUTES AND RESOLVED WITH SUPPORTIVE MEASURES; HOWEVER, SOME LASTED UP TO SEVERAL HOURS AND SOME REQUIRED EMERGENCY CARE AND/OR HOSPITALIZATION.
IN ADDITION TO SERIOUS POME REACTIONS, EPISODES OF ANAPHYLAXIS, INCLUDING LIFE-THREATENING REACTIONS, HAVE ALSO BEEN REPORTED TO OCCUR FOLLOWING THE INJECTION OF INTRAMUSCULAR TESTOSTERONE UNDECANOATE IN POST-APPROVAL USE OUTSIDE OF THE UNITED STATES.
BOTH SERIOUS POME REACTIONS AND ANAPHYLAXIS HAVE BEEN REPORTED TO OCCUR AFTER ANY INJECTION OF TESTOSTERONE UNDECANOATE DURING THE COURSE OF THERAPY, INCLUDING AFTER THE FIRST DOSE.
OTHER EVENTS
THE FOLLOWING TREATMENT EMERGENT ADVERSE EVENTS OR ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POST-MARKETING CLINICAL TRIALS AND DURING POST-APPROVAL USE OUTSIDE THE UNITED STATES OF INTRAMUSCULAR TESTOSTERONE UNDECANOATE. IN MOST CASES, THE DOSE BEING USED WAS 1000 MG.
BLOOD AND LYMPHATIC SYSTEM DISORDERS: POLYCYTHEMIA, THROMBOCYTOPENIA
CARDIAC DISORDERS: ANGINA PECTORIS, CARDIAC ARREST, CARDIAC FAILURE, CORONARY ARTERY DISEASE, CORONARY ARTERY OCCLUSION, MYOCARDIAL INFARCTION, TACHYCARDIA
EAR AND LABYRINTH DISORDERS: SUDDEN HEARING LOSS, TINNITUS
ENDOCRINE DISORDERS: HYPERPARATHYROIDISM, HYPOGLYCEMIA
GASTROINTESTINAL DISORDERS: ABDOMINAL PAIN UPPER, DIARRHEA, VOMITING
GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS: CHEST PAIN, EDEMA PERIPHERAL, INJECTION SITE DISCOMFORT, INJECTION SITE HEMATOMA, INJECTION SITE IRRITATION, INJECTION SITE PAIN, INJECTION SITE REACTION, MALAISE, PARESTHESIA, PROCEDURAL PAIN
IMMUNE SYSTEM DISORDERS: ANAPHYLACTIC REACTION, ANAPHYLACTIC SHOCK, ASTHMA, DERMATITIS ALLERGIC, HYPERSENSITIVITY, LEUKOCYTOCLASTIC VASCULITIS
INFECTIONS AND INFESTATIONS: INJECTION SITE ABSCESS, PROSTATE INFECTION
INVESTIGATIONS: ALANINE AMINOTRANSFERASE INCREASED, ASPARTATE AMINOTRANSFERASE INCREASED, BLOOD BILIRUBIN INCREASED, BLOOD GLUCOSE
INCREASED, BLOOD PRESSURE INCREASED, BLOOD PROLACTIN INCREASED, BLOOD TESTOSTERONE DECREASED, BLOOD TESTOSTERONE INCREASED, BLOOD TRIGLYCERIDES INCREASED, GAMMA-GLUTAMYLTRANSFERASE INCREASED, HEMATOCRIT INCREASED, INTRAOCULAR PRESSURE INCREASED, LIVER FUNCTION TEST ABNORMAL, PROSTATE EXAMINATION ABNORMAL, PROSTATIC SPECIFIC ANTIGEN INCREASED, TRANSAMINASES INCREASED
METABOLISM AND NUTRITION DISORDERS: DIABETES MELLITUS, FLUID RETENTION, HYPERLIPIDEMIA, HYPERTRIGLYCERIDEMIA
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: MUSCULOSKELETAL CHEST PAIN, MUSCULOSKELETAL PAIN, MYALGIA, OSTEOPENIA, OSTEOPOROSIS, SYSTEMIC LUPUS ERYTHEMATOSUS
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCLUDING CYSTS AND POLYPS): PROSTATE CANCER, PROSTATIC INTRAEPITHELIAL NEOPLASIA
NERVOUS SYSTEM DISORDERS: CEREBROVASCULAR INSUFFICIENCY, REVERSIBLE ISCHEMIC NEUROLOGICAL DEFICIENCY, TRANSIENT ISCHEMIC ATTACK
PSYCHIATRIC DISORDERS: AGGRESSION, ANXIETY, DEPRESSION, INSOMNIA, IRRITABILITY, KORSAKOFF'S PSYCHOSIS NON-ALCOHOLIC, MALE ORGASMIC DISORDER, NERVOUSNESS, RESTLESSNESS, SLEEP DISORDER
RENAL AND URINARY DISORDERS: CALCULUS URINARY, DYSURIA, HEMATURIA, NEPHROLITHIASIS, POLLAKIURIA, RENAL COLIC, RENAL PAIN, URINARY TRACT DISORDER
REPRODUCTIVE SYSTEM AND BREAST DISORDERS: BENIGN PROSTATIC HYPERPLASIA, BREAST INDURATION, BREAST PAIN, ERECTILE DYSFUNCTION,
GYNECOMASTIA, LIBIDO DECREASED, LIBIDO INCREASED, PROSTATE INDURATION, PROSTATITIS, SPERMATOCELE, TESTICULAR PAIN
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COUGH, DYSPHONIA, DYSPNEA,
HYPERVENTILATION, OBSTRUCTIVE AIRWAY DISORDER, PHARYNGEAL EDEMA, PHARYNGOLARYNGEAL PAIN, PULMONARY MICROEMBOLI, PULMONARY EMBOLISM, RESPIRATORY DISTRESS, RHINITIS, SLEEP APNEA SYNDROME, SNORING
SKIN AND SUBCUTANEOUS TISSUE DISORDERS: ACNE, ALOPECIA, ANGIOEDEMA, ANGIONEUROTIC EDEMA, DERMATITIS ALLERGIC, ERYTHEMA, HYPERHIDROSIS, PRURITUS, RASH
VASCULAR DISORDERS: CEREBRAL INFARCTION, CEREBROVASCULAR ACCIDENT, CIRCULATORY COLLAPSE, DEEP VENOUS THROMBOSIS, HOT FLUSH, HYPERTENSION, SYNCOPE, THROMBOEMBOLISM, THROMBOSIS, VENOUS INSUFFICIENCY.
READ THE AVEED (TESTOSTERONE UNDECANOATE INJECTION) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
THERE HAVE BEEN NO REPORTS OF OVERDOSAGE IN THE AVEED CLINICAL TRIALS. THERE IS ONE REPORT OF ACUTE OVERDOSAGE WITH USE OF AN APPROVED INJECTABLE TESTOSTERONE PRODUCT: THIS SUBJECT HAD SERUM TESTOSTERONE LEVELS OF UP TO 11,400 NG/DL WITH A CEREBROVASCULAR ACCIDENT.
TREATMENT OF OVERDOSAGE WOULD CONSIST OF DISCONTINUATION OF AVEED TOGETHER WITH APPROPRIATE SYMPTOMATIC AND SUPPORTIVE CARE.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
ENDOGENOUS ANDROGENS, INCLUDING TESTOSTERONE AND DIHYDROTESTOSTERONE (DHT) ARE RESPONSIBLE FOR THE NORMAL GROWTH AND DEVELOPMENT OF THE MALE SEX ORGANS AND FOR MAINTENANCE OF SECONDARY SEX CHARACTERISTICS. THESE EFFECTS INCLUDE THE GROWTH AND MATURATION OF PROSTATE, SEMINAL VESICLES, PENIS, AND SCROTUM; THE DEVELOPMENT OF MALE HAIR DISTRIBUTION, SUCH AS FACIAL, PUBIC, CHEST, AND AXILLARY HAIR; LARYNGEAL ENLARGEMENT, VOCAL CORD THICKENING, AND ALTERATIONS IN BODY MUSCULATURE AND FAT DISTRIBUTION.
MALE HYPOGONADISM, A CLINICAL SYNDROME RESULTING FROM INSUFFICIENT SECRETION OF TESTOSTERONE, HAS TWO MAIN ETIOLOGIES. PRIMARY HYPOGONADISM IS CAUSED BY DEFECTS OF THE GONADS, SUCH AS KLINEFELTER'S SYNDROME OR LEYDIG CELL APLASIA, WHEREAS SECONDARY HYPOGONADISM IS THE FAILURE OF THE HYPOTHALAMUS (OR PITUITARY) TO PRODUCE SUFFICIENT GONADOTROPINS (FSH, LH).
PHARMACOKINETICS
ABSORPTION
AVEED 750 MG DELIVERS PHYSIOLOGIC AMOUNTS OF TESTOSTERONE, PRODUCING CIRCULATION TESTOSTERONE CONCENTRATIONS THAT APPROXIMATE NORMAL CONCENTRATIONS (300-1000 NG/DL) SEEN IN HEALTHY MEN.
TESTOSTERONE ESTERS IN OIL INJECTED INTRAMUSCULARLY ARE ABSORBED FROM THE LIPID PHASE. CLEAVAGE OF THE UNDECANOIC ACID SIDE CHAIN OF AVEED BY TISSUE ESTERASES RELEASES TESTOSTERONE.
FOLLOWING INTRAMUSCULAR INJECTION OF 750 MG OF AVEED, SERUM TESTOSTERONE CONCENTRATIONS REACH A MAXIMUM AFTER A MEDIAN OF 7 DAYS (RANGE 4 - 42 DAYS) THEN SLOWLY DECLINE (FIGURE 3). STEADY STATE SERUM TESTOSTERONE CONCENTRATION WAS ACHIEVED WITH THE 3RD INJECTION OF AVEED AT 14 WEEKS.
FIGURE 3 SHOWS THE MEAN SERUM TOTAL TESTOSTERONE CONCENTRATION-TIME PROFILE DURING THE 3RD INJECTION INTERVAL (AT STEADY STATE, 14-24 WEEKS) FOR HYPOGONADAL MEN (LESS THAN 300 NG/DL) GIVEN 750 MG AVEED AT INITIATION, AT 4 WEEKS, AND EVERY 10 WEEKS THEREAFTER. INTRAMUSCULAR INJECTION OF 750 MG OF AVEED GENERATES MEAN STEADY STATE SERUM TOTAL TESTOSTERONE CONCENTRATIONS IN THE NORMAL RANGE FOR 10 WEEKS.
FIGURE 3: MEAN (SD) SERUM TOTAL TESTOSTERONE CONCENTRATIONS (NG/DL) AT 14-24 WEEKS
DISTRIBUTION
CIRCULATING TESTOSTERONE IS CHIEFLY BOUND IN THE SERUM TO SEX HORMONE-BINDING GLOBULIN (SHBG) AND ALBUMIN.
APPROXIMATELY 40% OF TESTOSTERONE IN PLASMA IS BOUND TO SHBG, 2% REMAINS UNBOUND (FREE), AND THE REST IS LOOSELY BOUND TO ALBUMIN AND OTHER PROTEINS.
METABOLISM
TESTOSTERONE UNDECANOATE IS METABOLIZED TO TESTOSTERONE VIA ESTER CLEAVAGE OF THE UNDECANOATE GROUP. THE MEAN (SD) MAXIMUM CONCENTRATION OF TESTOSTERONE UNDECANOATE WAS 90.9 (68.8) NG/DL ON DAY 4 FOLLOWING INJECTION OF AVEED. TESTOSTERONE UNDECANOATE WAS NEARLY UNDETECTABLE 42 DAYS FOLLOWING INJECTION OF AVEED.
TESTOSTERONE IS METABOLIZED TO VARIOUS 17-KETO STEROIDS THROUGH TWO DIFFERENT PATHWAYS. THE MAJOR ACTIVE METABOLITES OF TESTOSTERONE ARE ESTRADIOL AND DHT.
DHT CONCENTRATIONS INCREASED IN PARALLEL WITH TESTOSTERONE CONCENTRATIONS DURING AVEED TREATMENT. AVERAGE DHT CONCENTRATIONS DURING A DOSING INTERVAL RANGED FROM 244 TO 451 NG/DL. THE MEAN DHT:T RATIOS RANGED FROM 0.05 TO 0.07.
EXCRETION
THERE IS CONSIDERABLE VARIATION IN THE HALF-LIFE OF TESTOSTERONE AS REPORTED IN THE LITERATURE, RANGING FROM 10 TO 100 MINUTES. ABOUT 90% OF A TESTOSTERONE DOSE GIVEN INTRAMUSCULARLY IS EXCRETED IN THE URINE AS GLUCURONIC AND SULFURIC ACID-CONJUGATES OF TESTOSTERONE OR AS METABOLITES. ABOUT 6% OF A DOSE IS EXCRETED IN THE FECES, MOSTLY IN THE UNCONJUGATED FORM. INACTIVATION OF TESTOSTERONE OCCURS PRIMARILY IN THE LIVER.
EFFECT OF BODY WEIGHT AND BODY MASS INDEX (BMI)
ANALYSIS OF SERUM TESTOSTERONE CONCENTRATIONS FROM 117 HYPOGONADAL MEN IN THE 84-WEEK CLINICAL STUDY OF AVEED INDICATED THAT SERUM TESTOSTERONE CONCENTRATIONS ACHIEVED WERE INVERSELY CORRELATED WITH THE PATIENT'S BODY WEIGHT. IN 60 PATIENTS WITH PRETREATMENT BODY WEIGHT OF ? 100 KG, THE MEAN (±SD) SERUM TESTOSTERONE AVERAGE CONCENTRATION WAS 426 ± 104 NG/DL. A HIGHER SERUM TESTOSTERONE AVERAGE CONCENTRATION (568 ± 139 NG/DL) WAS OBSERVED IN 57 PATIENTS WEIGHING 65 TO 100 KG. A SIMILAR TREND WAS ALSO OBSERVED FOR MAXIMUM SERUM TESTOSTERONE CONCENTRATIONS.
IN 70 PATIENTS WITH PRETREATMENT BODY MASS INDEX OF > 30 KG/M², THE MEAN (±SD) SERUM TESTOSTERONE AVERAGE CONCENTRATION WAS 445 ± 116 NG/DL. HIGHER SERUM TESTOSTERONE AVERAGE CONCENTRATIONS (579 ± 101 NG/DL AND 567± 155NG/DL) WERE OBSERVED IN PATIENTS WITH BMIS < 26 KG/M² AND 26 TO 30 KG/M², RESPECTIVELY. A SIMILAR TREND WAS ALSO OBSERVED FOR MAXIMUM SERUM TESTOSTERONE CONCENTRATIONS.
CLINICAL STUDIES
TESTOSTERONE REPLACEMENT THERAPY
AVEED WAS EVALUATED FOR EFFICACY IN AN 84-WEEK, SINGLE-ARM, OPEN-LABEL, MULTICENTER STUDY OF 130 HYPOGONADAL MEN. ELIGIBLE PATIENTS WEIGHED AT LEAST 65 KG, WERE 18 YEARS OF AGE AND OLDER (MEAN AGE 54.2 YEARS), AND HAD A MORNING SERUM TOTAL TESTOSTERONE CONCENTRATION < 300 NG/DL (MEAN SCREENING TESTOSTERONE CONCENTRATION 215 NG/DL). PATIENTS WERE CAUCASIAN (74.6%), BLACK (12.3%), HISPANIC (10.8%) AND OF OTHER ETHNICITIES (2.3%). THE MEAN BODY MASS INDEX WAS 32 KG/M² .
ALL PATIENTS RECEIVED INJECTIONS OF AVEED 750 MG AT BASELINE, AT 4 WEEKS, AND THEN EVERY 10 WEEKS THEREAFTER.
THE PRIMARY ENDPOINT WAS THE PERCENTAGE OF PATIENTS WITH AVERAGE SERUM TOTAL TESTOSTERONE CONCENTRATION (CAVG) WITHIN THE NORMAL RANGE (300-1000 NG/DL) AFTER THE THIRD INJECTION, AT STEADY STATE.
THE SECONDARY ENDPOINT WAS THE PERCENTAGE OF PATIENTS WITH MAXIMUM TOTAL TESTOSTERONE CONCENTRATION (CMAX) ABOVE THREE PREDETERMINED LIMITS: GREATER THAN 1500 NG/DL, BETWEEN 1800 AND 2499 NG/DL, AND GREATER THAN 2500 NG/DL.
A TOTAL OF 117 OUT OF 130 HYPOGONADAL MEN COMPLETED STUDY PROCEDURES THROUGH WEEK 24 AND WERE INCLUDED IN THE EVALUATION OF TESTOSTERONE PHARMACOKINETICS AFTER THE THIRD AVEED INJECTION. NINETY-FOUR PERCENT (94%) OF PATIENTS MAINTAINED A CAVG WITHIN THE NORMAL RANGE (300 TO 1000 NG/DL). THE PERCENTAGES OF PATIENTS WITH CAVG BELOW THE NORMAL RANGE (LESS THAN 300 NG/DL) AND ABOVE THE NORMAL RANGE (GREATER THAN 1000 NG/DL) WERE 5.1% AND 0.9%, RESPECTIVELY.
TABLE 2 SUMMARIZES THE MEAN (SD) SERUM TOTAL TESTOSTERONE PHARMACOKINETIC PARAMETERS AT STEADY STATE FOR THESE 117 PATIENTS.
TABLE 2: MEAN (SD) SERUM TOTAL TESTOSTERONE CONCENTRATIONS AT STEADY STATE
AVEED 750 MG
(N=117)
CAVA (0 TO 10 WEEKS) (NG/DL) 495 (142)
CMAX (NG/DL) 891 (345)
CMIN (NG/DL) 324 (99)
CAVG = AVERAGE CONCENTRATION; CMAX = MAXIMUM CONCENTRATION; CMIN = MINIMUM CONCENTRATION
THE PERCENTAGE OF PATIENTS WITH CMAX > 1500 NG/DL WAS 7.7%. NO PATIENT HAD A CMAX > 1800 NG/DL.