TRESIBA®
(INSULIN DEGLUDEC) INJECTION
DESCRIPTION
TRESIBA (INSULIN DEGLUDEC INJECTION) IS A LONG-ACTING BASAL HUMAN INSULIN ANALOG FOR SUBCUTANEOUS INJECTION. INSULIN DEGLUDEC IS PRODUCED BY A PROCESS THAT INCLUDES EXPRESSION OF RECOMBINANT DNA IN SACCHAROMYCES CEREVISIAE FOLLOWED BY CHEMICAL MODIFICATION.
INSULIN DEGLUDEC DIFFERS FROM HUMAN INSULIN IN THAT THE AMINO ACID THREONINE IN POSITION B30 HAS BEEN OMITTED AND A SIDE-CHAIN CONSISTING OF GLUTAMIC ACID AND A C16 FATTY ACID HAS BEEN ATTACHED (CHEMICAL NAME: LYSB29(N?-HEXADECANDIOYL-?-GLU) DES(B30) HUMAN INSULIN). INSULIN DEGLUDEC HAS A MOLECULAR FORMULA OF C274H411N65O81S6 AND A MOLECULAR WEIGHT OF 6103.97. IT HAS THE FOLLOWING STRUCTURE:
TRESIBA IS A STERILE, AQUEOUS, CLEAR, AND COLORLESS SOLUTION THAT CONTAINS INSULIN DEGLUDEC 100 UNITS/ML (U100) OR 200 UNITS/ML (U-200).
FOR THE 100 UNITS/ML SOLUTION, EACH ML CONTAINS 100 UNITS (600 NMOL) OF INSULIN DEGLUDEC AND GLYCEROL (19.6 MG), METACRESOL (1.72 MG), PHENOL (1.50 MG), ZINC (32.7 MCG), AND WATER FOR INJECTION, USP.
FOR THE 200 UNITS/ML SOLUTION, EACH ML CONTAINS 200 UNITS (1200 NMOL) OF INSULIN DEGLUDEC AND GLYCEROL (19.6 MG), METACRESOL (1.72 MG), PHENOL (1.50 MG), ZINC (71.9 MCG), AND WATER FOR INJECTION, USP.
TRESIBA HAS A PH OF APPROXIMATELY 7.6. HYDROCHLORIC ACID OR SODIUM HYDROXIDE MAY BE ADDED TO ADJUST PH.
INDICATIONS & DOSAGE
INDICATIONS
TRESIBA IS INDICATED TO IMPROVE GLYCEMIC CONTROL IN PATIENTS 1 YEAR OF AGE AND OLDER WITH DIABETES MELLITUS.
LIMITATIONS OF USE
· NOT RECOMMENDED FOR THE TREATMENT OF DIABETIC KETOACIDOSIS.
DOSAGE AND ADMINISTRATION
IMPORTANT ADMINISTRATION INSTRUCTIONS
· ALWAYS CHECK INSULIN LABELS BEFORE ADMINISTRATION [SEE WARNINGS AND PRECAUTIONS ].
· INSPECT VISUALLY FOR PARTICULATE MATTER AND DISCOLORATION. ONLY USE TRESIBA IF THE SOLUTION APPEARS CLEAR AND COLORLESS.
· INJECT TRESIBA SUBCUTANEOUSLY INTO THE THIGH, UPPER ARM, OR ABDOMEN.
· ROTATE INJECTION SITES WITHIN THE SAME REGION FROM ONE INJECTION TO THE NEXT TO REDUCE THE RISK OF LIPODYSTROPHY [SEE ADVERSE REACTIONS ].
· FOR PEDIATRIC PATIENTS REQUIRING LESS THAN 5 UNITS OF TRESIBA EACH DAY, USE THE TRESIBA U-100 VIAL.
· USE TRESIBA WITH CAUTION IN PATIENTS WITH VISUAL IMPAIRMENT THAT MAY RELY ON AUDIBLE CLICKS TO DIAL THEIR DOSE.
· DO NOT ADMINISTER TRESIBA INTRAVENOUSLY OR IN AN INSULIN INFUSION PUMP.
· DO NOT DILUTE OR MIX TRESIBA WITH ANY OTHER INSULIN PRODUCTS OR SOLUTIONS.
· DO NOT TRANSFER TRESIBA FROM THE TRESIBA PEN INTO A SYRINGE FOR ADMINISTRATION [SEE WARNINGS AND PRECAUTIONS ].
GENERAL DOSING INSTRUCTIONS
· TRESIBA IS AVAILABLE IN 2 CONCENTRATIONS (U-100 AND U-200):
o TRESIBA U-100 CONCENTRATION IS AVAILABLE IN 2 PRESENTATIONS, FLEXTOUCH PEN AND VIAL
§ TRESIBA U-100 SINGLE-PATIENT-USE FLEXTOUCH PEN CONTAINS 300 UNITS OF TRESIBA U-100. IT DELIVERS DOSES IN 1 UNIT INCREMENTS AND CAN DELIVER UP TO 80 UNITS IN A SINGLE INJECTION.
§ TRESIBA U-100 MULTIPLE-DOSE VIAL CONTAINS 1000 UNITS OF TRESIBA U-100. USE VIAL ONLY WITH A U-100 INSULIN SYRINGE.
o TRESIBA U-200 CONCENTRATION IS ONLY AVAILABLE IN A FLEXTOUCH PEN
§ TRESIBA U-200 SINGLE-PATIENT-USE FLEXTOUCH PEN CONTAINS 600 UNITS OF TRESIBA U-200. IT DELIVERS DOSES IN 2 UNIT INCREMENTS AND CAN DELIVER UP TO 160 UNITS IN A SINGLE INJECTION.
· DO NOT PERFORM DOSE CONVERSION WHEN USING THE TRESIBA U-100 OR U-200 PENS. THE DOSE WINDOW SHOWS THE NUMBER OF INSULIN UNITS TO BE DELIVERED AND NO CONVERSION IS NEEDED.
· IN ADULTS, INJECT TRESIBA SUBCUTANEOUSLY ONCE-DAILY AT ANY TIME OF DAY.
· IN PEDIATRIC PATIENTS INJECT TRESIBA SUBCUTANEOUSLY ONCE-DAILY AT THE SAME TIME EVERY DAY.
· INDIVIDUALIZE AND TITRATE THE DOSE OF TRESIBA BASED ON THE PATIENT'S METABOLIC NEEDS, BLOOD GLUCOSE MONITORING RESULTS, AND GLYCEMIC CONTROL GOAL.
· THE RECOMMENDED DAYS BETWEEN DOSE INCREASES ARE 3 TO 4 DAYS.
· DOSE ADJUSTMENTS MAY BE NEEDED WITH CHANGES IN PHYSICAL ACTIVITY, CHANGES IN MEAL PATTERNS (I.E., MACRONUTRIENT CONTENT OR TIMING OF FOOD INTAKE), CHANGES IN RENAL OR HEPATIC FUNCTION OR DURING ACUTE ILLNESS TO MINIMIZE THE RISK OF HYPOGLYCEMIA OR HYPERGLYCEMIA [SEE WARNINGS AND PRECAUTIONS ].
· FOR ADULT PATIENTS, INSTRUCT PATIENTS WHO MISS A DOSE OF TRESIBA TO INJECT THEIR DAILY DOSE DURING WAKING HOURS UPON DISCOVERING THE MISSED DOSE. INSTRUCT PATIENTS TO ENSURE THAT AT LEAST 8 HOURS HAVE ELAPSED BETWEEN CONSECUTIVE TRESIBA INJECTIONS.
· FOR PEDIATRIC PATIENTS, INSTRUCT PATIENTS WHO MISS A DOSE OF TRESIBA TO CONTACT THEIR HEALTHCARE PROVIDER FOR GUIDANCE AND TO MONITOR BLOOD GLUCOSE LEVELS MORE FREQUENTLY UNTIL THE NEXT SCHEDULED TRESIBA DOSE.
STARTING DOSE IN INSULIN NAIVE PATIENTS
TYPE 1 DIABETES MELLITUS
THE RECOMMENDED STARTING DOSE OF TRESIBA IN INSULIN NAIVE PATIENTS WITH TYPE 1 DIABETES IS APPROXIMATELY ONE-THIRD TO ONE-HALF OF THE TOTAL DAILY INSULIN DOSE. THE REMAINDER OF THE TOTAL DAILY INSULIN DOSE SHOULD BE ADMINISTERED AS A SHORT-ACTING INSULIN AND DIVIDED BETWEEN EACH DAILY MEAL. AS A GENERAL RULE, 0.2 TO 0.4 UNITS OF INSULIN PER KILOGRAM OF BODY WEIGHT CAN BE USED TO CALCULATE THE INITIAL TOTAL DAILY INSULIN DOSE IN INSULIN NAIVE PATIENTS WITH TYPE 1 DIABETES .
TYPE 2 DIABETES MELLITUS
THE RECOMMENDED STARTING DOSE OF TRESIBA IN INSULIN NAIVE PATIENTS WITH TYPE 2 DIABETES MELLITUS IS 10 UNITS ONCE DAILY.
STARTING DOSE IN PATIENTS ALREADY ON INSULIN THERAPY
ADULTS WITH TYPE 1 OR TYPE 2 DIABETES MELLITUS
START TRESIBA AT THE SAME UNIT DOSE AS THE TOTAL DAILY LONG OR INTERMEDIATE-ACTING INSULIN UNIT DOSE.
PEDIATRIC PATIENTS 1 YEAR OF AGE AND OLDER WITH TYPE 1 OR TYPE 2 DIABETES MELLITUS
START TRESIBA AT 80% OF THE TOTAL DAILY LONG OR INTERMEDIATE-ACTING INSULIN UNIT DOSE TO MINIMIZE THE RISK OF HYPOGLYCEMIA [SEE WARNINGS AND PRECAUTIONS ].
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
INJECTION: TRESIBA IS AVAILABLE AS A CLEAR AND COLORLESS SOLUTION:
· 100 UNITS/ML (U-100): 3 ML SINGLE-PATIENT-USE FLEXTOUCH DISPOSABLE PREFILLED PEN
· 100 UNITS/ML (U-100): 10 ML MULTIPLE-DOSE VIAL
· 200 UNITS/ML (U-200): 3 ML SINGLE-PATIENT-USE FLEXTOUCH DISPOSABLE PREFILLED PEN
STORAGE AND HANDLING
TRESIBA INJECTION IS AVAILABLE AS A CLEAR AND COLORLESS SOLUTION IN THE FOLLOWING PACKAGE SIZES (SEE TABLE 17).
TABLE 17: PRESENTATIONS OF TRESIBA
TRESIBA PRESENTATION TOTAL VOLUME CONCENTRATION TOTAL UNITS AVAILABLE IN PRESENTATION NDC NUMBER MAX DOSE PER INJECTION DOSE INCREMENT PACKAGE SIZE
U-100 SINGLE-PATIENT-USE FLEXTOUCH PEN 3 ML 100 UNITS/ML 300 UNITS 0169-2660-15 80 UNITS 1 UNIT 5 PENS/PACK
U-100 MULTIPLE-DOSE VIAL 10 ML 100 UNITS/ML 1,000 UNITS 0169-2662-11 - - 1 VIAL/PACK
U-200 SINGLE-PATIENT-USE FLEXTOUCH PEN 3 ML 200 UNITS/ML 600 UNITS 0169-2550-13 160 UNITS 2 UNIT 3 PENS/PACK
TRESIBA U-100 FLEXTOUCH DIALS IN 1 UNIT INCREMENTS.
TRESIBA U-200 FLEXTOUCH DIALS IN 2 UNIT INCREMENTS.
RECOMMENDED STORAGE
STORE TRESIBA VIALS IN THE ORIGINAL CARTON TO PROTECT FROM LIGHT. UNUSED TRESIBA SHOULD BE STORED IN A REFRIGERATOR (36°F TO 46°F [2°C TO 8°C]). DO NOT STORE IN THE FREEZER OR DIRECTLY ADJACENT TO THE REFRIGERATOR COOLING ELEMENT. DO NOT FREEZE. DO NOT USE TRESIBA IF IT HAS BEEN FROZEN.
THE STORAGE CONDITIONS ARE SUMMARIZED IN TABLE 18:
TABLE 18: STORAGE CONDITIONS FOR TRESIBA
NOT IN-USE (UNOPENED) IN-USE (OPENED)
REFRIGERATED (36°F TO 46°F [2°C TO 8°C]) ROOM TEMPERATURE (BELOW 86°F [30°C]) ROOM TEMPERATURE (BELOW 86°F [30°C]) REFRIGERATED (36°F TO 46°F [2°C TO 8°C])
3 ML TRESIBA U-100 FLEXTOUCH UNTIL EXPIRATION DATE 56 DAYS (8 WEEKS) 56 DAYS (8 WEEKS) 56 DAYS (8 WEEKS)
10 ML TRFSIBAU-100 VIAL UNTIL EXPIRATION DATE 56 DAYS (8 WEEKS) 56 DAYS (8 WEEKS) 56 DAYS (8 WEEKS)
3 ML TRESIBA U-200 FLEXTOUCH UNTIL EXPIRATION DATE 56 DAYS (8 WEEKS) 56 DAYS (8 WEEKS) 56 DAYS (8 WEEKS)
SIDE EFFECTS
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE ALSO DISCUSSED ELSEWHERE:
· HYPOGLYCEMIA [SEE WARNINGS AND PRECAUTIONS ]
· MEDICATION ERRORS [SEE WARNINGS AND PRECAUTIONS ]
· HYPERSENSITIVITY AND ALLERGIC REACTIONS [SEE WARNINGS AND PRECAUTIONS ]
· HYPOKALEMIA [SEE WARNINGS AND PRECAUTIONS ]
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 PRACTICE.
THE SAFETY OF TRESIBA IN SUBJECTS WITH TYPE 1 DIABETES OR TYPE 2 DIABETES WAS EVALUATED IN NINE TRIALS OF 6-12 MONTH DURATION IN ADULTS AND IN ONE TRIAL OF 12-MONTH DURATION IN PEDIATRIC PATIENTS 1 YEAR OF AGE AND OLDER WITH TYPE 1 DIABETES. THE CARDIOVASCULAR SAFETY OF TRESIBA WAS EVALUATED IN ONE DOUBLE-BLINDED, EVENT-DRIVEN TRIAL OF 2-YEAR MEDIAN DURATION IN PATIENTS WITH TYPE 2 DIABETES AT HIGH RISK OF CARDIOVASCULAR EVENTS [SEE CLINICAL STUDIES ].
THE DATA IN TABLE 1 REFLECT THE EXPOSURE OF 1102 ADULTS WITH TYPE 1 DIABETES TO TRESIBA WITH A MEAN EXPOSURE DURATION TO TRESIBA OF 34 WEEKS IN THREE OPEN-LABEL TRIALS. THE MEAN AGE WAS 43 YEARS AND 1% WERE OLDER THAN 75 YEARS. FIFTY-SEVEN PERCENT WERE MALE, 81% WERE WHITE, 2% WERE BLACK OR AFRICAN AMERICAN AND 4% WERE HISPANIC. THE MEAN BODY MASS INDEX (BMI ) WAS 26 KG/M². THE MEAN DURATION OF DIABETES WAS 18 YEARS AND THE MEAN HBA1C AT BASELINE WAS 7.8%. A HISTORY OF NEUROPATHY , OPHTHALMOPATHY , NEPHROPATHY AND CARDIOVASCULAR DISEASE AT BASELINE WAS REPORTED IN 11%, 16%, 7% AND 0.5% RESPECTIVELY. THE MEAN EGFR AT BASELINE WAS 87 ML/MIN/1.73 M² AND 7% OF THE PATIENTS HAD AN EGFR LESS THAN 60 ML/MIN/1.73 M².
THE DATA IN TABLE 2 REFLECT THE EXPOSURE OF 2713 ADULTS WITH TYPE 2 DIABETES TO TRESIBA WITH A MEAN EXPOSURE DURATION TO TRESIBA OF 36 WEEKS IN SIX OPEN-LABEL TRIALS. THE MEAN AGE WAS 58 YEARS AND 3% WERE OLDER THAN 75 YEARS. FIFTY-EIGHT PERCENT WERE MALE, 71% WERE WHITE, 7% WERE BLACK OR AFRICAN AMERICAN AND 13% WERE HISPANIC. THE MEAN BMI WAS 30 KG/M². THE MEAN DURATION OF DIABETES WAS 11 YEARS AND THE MEAN HBA1C AT BASELINE WAS 8.3%. A HISTORY OF NEUROPATHY, OPHTHALMOPATHY, NEPHROPATHY AND CARDIOVASCULAR DISEASE AT BASELINE WAS REPORTED FOR 14%, 10%, 6% AND 0.6% OF PARTICIPANTS RESPECTIVELY. AT BASELINE, THE MEAN EGFR WAS 83 ML/MIN/1.73 M² AND 9% HAD AN EGFR LESS THAN 60 ML/MIN/1.73 M².
COMMON ADVERSE REACTIONS (EXCLUDING HYPOGLYCEMIA) OCCURRING IN TRESIBA TREATED SUBJECTS DURING CLINICAL TRIALS IN ADULT PATIENTS WITH TYPE 1 DIABETES MELLITUS AND ADULTS WITH TYPE 2 DIABETES MELLITUS ARE LISTED IN TABLE 1 AND TABLE 2, RESPECTIVELY. COMMON ADVERSE REACTIONS WERE DEFINED AS REACTIONS OCCURRING IN ?5% OF THE POPULATION STUDIED. HYPOGLYCEMIA IS NOT SHOWN IN THESE TABLES BUT DISCUSSED IN A DEDICATED SUBSECTION BELOW.
174 PEDIATRIC PATIENTS 1 YEAR OF AGE AND OLDER WITH TYPE 1 DIABETES WERE EXPOSED TO TRESIBA WITH A MEAN EXPOSURE TO TRESIBA OF 48 WEEKS. THE MEAN AGE WAS 10 YEARS: 25% WERE AGES 1-5 YEARS, 40% WERE AGES 6-11 YEARS, AND 35% WERE AGES 12-17 YEARS. 55.2% WERE MALE, 78.2% WERE WHITE, 2.9% WERE BLACK OR AFRICAN AMERICAN AND 4% WERE HISPANIC. THE MEAN BODY MASS INDEX (BMI) WAS 18.7 KG/M². THE MEAN DURATION OF DIABETES WAS 3.9 YEARS AND THE MEAN HBA1C AT BASELINE WAS 8.2%. COMMON ADVERSE REACTIONS IN TRESIBA TREATED PEDIATRIC PATIENTS WITH TYPE 1 DIABETES MELLITUS WERE SIMILAR TO THE ADVERSE REACTIONS LISTED IN TABLE 1.
TABLE 1: ADVERSE REACTIONS OCCURRING IN ?5% OF TRESIBA-TREATED ADULT PATIENTS WITH TYPE 1 DIABETES MELLITUS
ADVERSE REACTION TRESIBA (N=1102)
NASOPHARYNGITIS 23.9 %
UPPER RESPIRATORY TRACT INFECTION 11.9 %
HEADACHE 11.8 %
SINUSITIS 5.1 %
GASTROENTERITIS 5.1 %
TABLE 2: ADVERSE REACTIONS OCCURRING IN ?5% OF TRESIBA-TREATED ADULT PATIENTS WITH TYPE 2 DIABETES MELLITUS
ADVERSE REACTION TRESIBA (N=2713)
NASOPHARYNGITIS 12.9 %
HEADACHE 8.8 %
UPPER RESPIRATORY TRACT INFECTION 8.4 %
DIARRHEA 6.3 %
HYPOGLYCEMIA
HYPOGLYCEMIA IS THE MOST COMMONLY OBSERVED ADVERSE REACTION IN PATIENTS USING INSULIN, INCLUDING TRESIBA [SEE WARNINGS AND PRECAUTIONS ]. THE RATES OF REPORTED HYPOGLYCEMIA DEPEND ON THE DEFINITION OF HYPOGLYCEMIA USED, DIABETES TYPE, INSULIN DOSE, INTENSITY OF GLUCOSE CONTROL, BACKGROUND THERAPIES, AND OTHER INTRINSIC AND EXTRINSIC PATIENT FACTORS. FOR THESE REASONS, COMPARING RATES OF HYPOGLYCEMIA IN CLINICAL TRIALS FOR TRESIBA WITH THE INCIDENCE OF HYPOGLYCEMIA FOR OTHER PRODUCTS MAY BE MISLEADING AND ALSO, MAY NOT BE REPRESENTATIVE OF HYPOGLYCEMIA RATES THAT WILL OCCUR IN CLINICAL PRACTICE.
IN THE OPEN-LABEL ADULT CLINICAL TRIALS OF PATIENTS WITH TYPE 1 AND TYPE 2 DIABETES, AND IN THE OPEN-LABEL PEDIATRIC CLINICAL TRIAL OF PATIENTS WITH TYPE 1 DIABETES, PERCENTAGES OF ADULT AND PEDIATRIC PATIENTS WITH TYPE 1 DIABETES RANDOMIZED TO TRESIBA WHO EXPERIENCED AT LEAST ONE EPISODE OF HYPOGLYCEMIA IN CLINICAL TRIALS [SEE CLINICAL STUDIES ] AND ADULTS WITH TYPE 2 DIABETES ARE SHOWN IN TABLES 3 AND 4, RESPECTIVELY.
SEVERE HYPOGLYCEMIA IN THE OPEN-LABEL TRIALS WITH ADULT PATIENTS WAS DEFINED AS AN EPISODE REQUIRING ASSISTANCE OF ANOTHER PERSON TO ACTIVELY ADMINISTER CARBOHYDRATE , GLUCAGON, OR OTHER RESUSCITATIVE ACTIONS. SEVERE HYPOGLYCEMIA IN THE PEDIATRIC TRIAL WAS DEFINED AS AN ALTERED MENTAL STATUS WHERE THE CHILD COULD NOT ASSIST IN HIS OWN CARE, WAS SEMICONSCIOUS OR UNCONSCIOUS , OR IN A COMA ± CONVULSIONS AND MAY REQUIRE PARENTERAL THERAPY (GLUCAGON OR INTRAVENOUS GLUCOSE). A NOVO NORDISK HYPOGLYCEMIA EPISODE WAS DEFINED AS A SEVERE HYPOGLYCEMIA EPISODE OR AN EPISODE WHERE A LABORATORY OR A SELF-MEASURED GLUCOSE CALIBRATED TO PLASMA WAS LESS THAN 56 MG/DL OR WHERE A WHOLE BLOOD GLUCOSE WAS LESS THAN 50 MG/DL (I.E., WITH OR WITHOUT THE PRESENCE OF HYPOGLYCEMIC SYMPTOMS).
TABLE 3: PERCENT (%) OF TYPE 1 DIABETES PATIENTS EXPERIENCING AT LEAST ONE EPISODE OF SEVERE HYPOGLYCEMIA OR NOVO NORDISK HYPOGLYCEMIA§ ON TRESIBA IN OPEN-LABEL ADULT AND PEDIATRIC CLINICAL TRIALS
STUDY A ADULTS + INSULIN ASPART 52 WEEKS STUDY B ADULTS + INSULIN ASPART 26 WEEKS STUDY C ADULTS + INSULIN ASPART 26 WEEKS STUDY J PEDIATRICS + INSULIN ASPART 52 WEEKS
TRESIBA (N=472) TRESIBA (N=301) TRESIBA AT THE SAME TIME EACH DAY (N=165) TRESIBA AT ALTERNATING TIMES (N=164) TRESIBA (N=174)
SEVERE HYPOGLYCEMIA*
PERCENT OF PATIENTS 12.3% 10.6% 12.7% 10.4% 17.8%
NOVO NORDISK HYPOGLYCEMIA§
PERCENT OF PATIENTS 95.6% 93.0% 99.4% 93.9% 98.3%
*SEVERE HYPOGLYCEMIA IN PEDIATRIC PATIENTS: AN EPISODE WITH ALTERED MENTAL STATUS, WHERE THE CHILD COULD NOT ASSIST IN HIS OWN CARE, WAS SEMICONSCIOUS OR UNCONSCIOUS, OR IN A COMA ± CONVULSIONS AND MAY REQUIRE PARENTERAL THERAPY (GLUCAGON OR INTRAVENOUS GLUCOSE). §NOVO NORDISK HYPOGLYCEMIA: A SEVERE HYPOGLYCEMIA EPISODE OR AN EPISODE WHERE A LABORATORY OR A SELF-MEASURED GLUCOSE CALIBRATED TO PLASMA WAS LESS THAN 56 MG/DL OR WHERE A WHOLE BLOOD GLUCOSE WAS LESS THAN 50 MG/DL (I.E., WITH OR WITHOUT THE PRESENCE OF HYPOGLYCEMIC SYMPTOMS).
TABLE 4: PERCENT (%) OF PATIENTS WITH TYPE 2 DIABETES EXPERIENCING AT LEAST ONE EPISODE OF SEVERE HYPOGLYCEMIA OR NOVO NORDISK HYPOGLYCEMIA§ ON TRESIBA IN OPEN-LABEL ADULT CLINICAL TRIALS
STUDY D + 1-2 OADS* INSULIN NAIVE 52 WEEKS STUDY E + 1-2 OADS* INSULIN NAIVE 26 WEEKS STUDY F ± 1-3 OADS* INSULIN NAIVE 26 WEEKS STUDY G T2DM ± 0-3 OADS* 26 WEEKS STUDY H T2DM ± 0-2 OADS* + INSULIN ASPART 52 WEEKS STUDY I T2DM ± 1-2 OADS* INSULIN NAIVE 26 WEEKS
TRESIBA (N=766) TRESIBA (N=228) TRESIBA (N=284) TRESIBA (N=226) TRESIBA (ALTERNATING TIME) (N=230) TRESIBA (N=753) TRESIBA (N=226)
SEVERE HYPOGLYCEMIA
PERCENT OF PATIENTS 0.3% 0 0 0.9% 0.4% 4.5% 0.4%
NOVO NORDISK HYPOGLYCEMIA§
PERCENT OF PATIENTS 46.5% 28.5% 50% 43.8% 50.9% 80.9% 42.5%
*OAD: ORAL ANTIDIABETIC AGENT, §NOVO NORDISK HYPOGLYCEMIA: A SEVERE HYPOGLYCEMIA EPISODE OR AN EPISODE WHERE A LABORATORY OR A SELF-MEASURED GLUCOSE CALIBRATED TO PLASMA WAS LESS THAN 56 MG/DL OR WHERE A WHOLE BLOOD GLUCOSE WAS LESS THAN 50 MG/DL (I.E., WITH OR WITHOUT THE PRESENCE OF HYPOGLYCEMIC SYMPTOMS).
ALLERGIC REACTIONS
SEVERE, LIFE-THREATENING, GENERALIZED ALLERGY, INCLUDING ANAPHYLAXIS, GENERALIZED SKIN REACTIONS, ANGIOEDEMA, BRONCHOSPASM, HYPOTENSION, AND SHOCK MAY OCCUR WITH ANY INSULIN, INCLUDING TRESIBA AND MAY BE LIFE THREATENING [SEE WARNINGS AND PRECAUTIONS ]. HYPERSENSITIVITY (MANIFESTED WITH SWELLING OF TONGUE AND LIPS, DIARRHEA, NAUSEA, TIREDNESS, AND ITCHING) AND URTICARIA WERE REPORTED IN 0.9% OF PATIENTS TREATED WITH TRESIBA.
LIPODYSTROPHY
LONG-TERM USE OF INSULIN, INCLUDING TRESIBA, CAN CAUSE LIPODYSTROPHY AT THE SITE OF REPEATED INSULIN INJECTIONS. LIPODYSTROPHY INCLUDES LIPOHYPERTROPHY (THICKENING OF ADIPOSE TISSUE) AND LIPOATROPHY (THINNING OF ADIPOSE TISSUE) AND MAY AFFECT INSULIN ABSORPTION [SEE DOSAGE AND ADMINISTRATION ]. IN THE CLINICAL PROGRAM, LIPODYSTROPHY, LIPOHYPERTROPHY, OR LIPOATROPHY WAS REPORTED IN 0.3% OF PATIENTS TREATED WITH TRESIBA.
INJECTION SITE REACTIONS
PATIENTS TAKING TRESIBA MAY EXPERIENCE INJECTION SITE REACTIONS, INCLUDING INJECTION SITE HEMATOMA, PAIN, HEMORRHAGE, ERYTHEMA, NODULES, SWELLING, DISCOLORATION, PRURITUS, WARMTH, AND INJECTION SITE MASS. IN THE CLINICAL PROGRAM, INJECTION SITE REACTIONS OCCURRED IN 3.8% OF PATIENTS TREATED WITH TRESIBA.
WEIGHT GAIN
WEIGHT GAIN CAN OCCUR WITH INSULIN THERAPY, INCLUDING TRESIBA, AND HAS BEEN ATTRIBUTED TO THE ANABOLIC EFFECTS OF INSULIN. IN THE CLINICAL PROGRAM AFTER 52 WEEKS OF TREATMENT, PATIENTS WITH TYPE 1 DIABETES TREATED WITH TRESIBA GAINED AN AVERAGE OF 1.8 KG AND PATIENTS WITH TYPE 2 DIABETES TREATED WITH TRESIBA GAINED AN AVERAGE OF 3.0 KG.
PERIPHERAL EDEMA
INSULIN, INCLUDING TRESIBA, MAY CAUSE SODIUM RETENTION AND EDEMA. IN THE CLINICAL PROGRAM, PERIPHERAL EDEMA OCCURRED IN 0.9% OF PATIENTS WITH TYPE 1 DIABETES MELLITUS AND 3.0% OF PATIENTS WITH TYPE 2 DIABETES MELLITUS TREATED WITH TRESIBA.
IMMUNOGENICITY
AS WITH ALL THERAPEUTIC PROTEINS, INSULIN ADMINISTRATION MAY CAUSE ANTI-INSULIN ANTIBODIES TO FORM. THE DETECTION OF ANTIBODY FORMATION IS HIGHLY DEPENDENT ON THE SENSITIVITY AND SPECIFICITY OF THE ASSAY AND MAY BE INFLUENCED BY SEVERAL FACTORS SUCH AS: ASSAY METHODOLOGY, SAMPLE HANDLING, TIMING OF SAMPLE COLLECTION, CONCOMITANT MEDICATION, AND UNDERLYING DISEASE. FOR THESE REASONS, COMPARISON OF THE INCIDENCE OF ANTIBODIES TO TRESIBA WITH THE INCIDENCE OF ANTIBODIES IN OTHER STUDIES OR TO OTHER PRODUCTS MAY BE MISLEADING.
IN A 52-WEEK STUDY OF ADULT INSULIN-EXPERIENCED TYPE 1 DIABETES PATIENTS, 68.9% OF PATIENTS WHO RECEIVED TRESIBA WERE POSITIVE AT BASELINE FOR ANTI-INSULIN DEGLUDEC ANTIBODIES AND 12.3% OF THE PATIENTS DEVELOPED ANTI-INSULIN DEGLUDEC ANTIBODIES AT LEAST ONCE DURING THE STUDY. IN A 52-WEEK STUDY OF PEDIATRIC INSULIN-EXPERIENCED TYPE 1 DIABETES PATIENTS, 84.1% OF PATIENTS WHO RECEIVED TRESIBA WERE POSITIVE AT BASELINE FOR ANTI-INSULIN DEGLUDEC ANTIBODIES AND 5.8% OF PATIENTS DEVELOPED ANTI-INSULIN DEGLUDEC ANTIBODIES AT LEAST ONCE DURING THE STUDY. IN A 52-WEEK STUDY OF ADULT INSULIN-NAIVE TYPE 2 DIABETES PATIENTS, 1.7% OF PATIENTS WHO RECEIVED TRESIBA WERE POSITIVE AT BASELINE FOR ANTI-INSULIN DEGLUDEC ANTIBODIES AND 6.2% OF PATIENTS DEVELOPED ANTI-INSULIN DEGLUDEC ANTIBODIES AT LEAST ONCE DURING THE STUDY. IN THESE TRIALS, BETWEEN 96.7% AND 99.7% OF PATIENTS WHO WERE POSITIVE FOR ANTI-INSULIN DEGLUDEC ANTIBODIES WERE ALSO POSITIVE FOR ANTI-HUMAN INSULIN ANTIBODIES.
DRUG INTERACTIONS
DRUG INTERACTIONS
TABLE 5 INCLUDES CLINICALLY SIGNIFICANT DRUG INTERACTIONS WITH TRESIBA.
TABLE 5: CLINICALLY SIGNIFICANT DRUG INTERACTIONS WITH TRESIBA
DRUGS THAT MAY INCREASE THE RISK OF HYPOGLYCEMIA
DRUGS: ANTIDIABETIC AGENTS, ACE INHIBITORS, ANGIOTENSIN II RECEPTOR BLOCKING AGENTS, DISOPYRAMIDE, FIBRATES, FLUOXETINE, MONOAMINE OXIDASE INHIBITORS, PENTOXIFYLLINE, PRAMLINTIDE, PROPOXYPHENE, SALICYLATES, SOMATOSTATIN ANALOGS (E.G., OCTREOTIDE), AND SULFONAMIDE ANTIBIOTICS, GLP-1 RECEPTOR AGONISTS, DPP-4 INHIBITORS, SGLT-2 INHIBITORS.
INTERVENTION: DOSE REDUCTIONS AND INCREASED FREQUENCY OF GLUCOSE MONITORING MAY BE REQUIRED WHEN TRESIBA IS COADMINISTERED WITH THESE DRUGS.
DRUGS THAT MAY DECREASE THE BLOOD GLUCOSE LOWERING EFFECT OF TRESIBA
DRUGS: ATYPICAL ANTIPSYCHOTICS (E.G., OLANZAPINE AND CLOZAPINE), CORTICOSTEROIDS, DANAZOL, DIURETICS, ESTROGENS, GLUCAGON, ISONIAZID, NIACIN, ORAL CONTRACEPTIVES, PHENOTHIAZINES, PROGESTOGENS (E.G., IN ORAL CONTRACEPTIVES), PROTEASE INHIBITORS, SOMATROPIN, SYMPATHOMIMETIC AGENTS (E.G., ALBUTEROL, EPINEPHRINE, TERBUTALINE), AND THYROID HORMONES.
INTERVENTION: DOSE INCREASES AND INCREASED FREQUENCY OF GLUCOSE MONITORING MAY BE REQUIRED WHEN TRESIBA IS COADMINISTERED WITH THESE DRUGS.
DRUGS THAT MAY INCREASE OR DECREASE THE BLOOD GLUCOSE LOWERING EFFECT OF TRESIBA
DRUGS: ALCOHOL, BETA-BLOCKERS, CLONIDINE, AND LITHIUM SALTS. PENTAMIDINE MAY CAUSE HYPOGLYCEMIA, WHICH MAY SOMETIMES BE FOLLOWED BY HYPERGLYCEMIA.
INTERVENTION: DOSE ADJUSTMENT AND INCREASED FREQUENCY OF GLUCOSE MONITORING MAY BE REQUIRED WHEN TRESIBA IS COADMINISTERED WITH THESE DRUGS.
DRUGS THAT MAY BLUNT SIGNS AND SYMPTOMS OF HYPOGLYCEMIA
DRUGS: BETA-BLOCKERS, CLONIDINE, GUANETHIDINE, AND RESERPINE
INTERVENTION: INCREASED FREQUENCY OF GLUCOSE MONITORING MAY BE REQUIRED WHEN TRESIBA IS CO-ADMINISTERED WITH THESE DRUGS.
WARNINGS & PRECAUTIONS
WARNINGS
INCLUDED AS PART OF THE PRECAUTIONS SECTION.
PRECAUTIONS
NEVER SHARE A TRESIBA FLEXTOUCH PEN, NEEDLE, OR SYRINGE BETWEEN PATIENTS
TRESIBA FLEXTOUCH DISPOSABLE PREFILLED PENS SHOULD NEVER BE SHARED BETWEEN PATIENTS, EVEN IF THE NEEDLE IS CHANGED. PATIENTS USING TRESIBA VIALS SHOULD NEVER SHARE NEEDLES OR SYRINGES WITH ANOTHER PERSON. SHARING POSES A RISK FOR TRANSMISSION OF BLOOD-BORNE PATHOGENS.
HYPERGLYCEMIA OR HYPOGLYCEMIA WITH CHANGES IN INSULIN REGIMEN
CHANGES IN INSULIN, MANUFACTURER, TYPE, OR METHOD OF ADMINISTRATION MAY AFFECT GLYCEMIC CONTROL AND PREDISPOSE TO HYPOGLYCEMIA OR HYPERGLYCEMIA. THESE CHANGES SHOULD BE MADE CAUTIOUSLY AND ONLY UNDER MEDICAL SUPERVISION AND THE FREQUENCY OF BLOOD GLUCOSE MONITORING SHOULD BE INCREASED. FOR PATIENTS WITH TYPE 2 DIABETES, ADJUSTMENTS IN CONCOMITANT ANTI-DIABETIC TREATMENT MAY BE NEEDED. WHEN CONVERTING FROM OTHER INSULIN THERAPIES TO TRESIBA FOLLOW DOSING RECOMMENDATIONS [SEE DOSAGE AND ADMINISTRATION ].
HYPOGLYCEMIA
HYPOGLYCEMIA IS THE MOST COMMON ADVERSE REACTION OF INSULIN, INCLUDING TRESIBA [SEE ADVERSE REACTIONS ]. SEVERE HYPOGLYCEMIA CAN CAUSE SEIZURES, MAY BE LIFE-THREATENING OR CAUSE DEATH. HYPOGLYCEMIA CAN IMPAIR CONCENTRATION ABILITY AND REACTION TIME; THIS MAY PLACE AN INDIVIDUAL AND OTHERS AT RISK IN SITUATIONS WHERE THESE ABILITIES ARE IMPORTANT (E.G., DRIVING OR OPERATING OTHER MACHINERY). TRESIBA, OR ANY INSULIN, SHOULD NOT BE USED DURING EPISODES OF HYPOGLYCEMIA [SEE CONTRAINDICATIONS ].
HYPOGLYCEMIA CAN HAPPEN SUDDENLY AND SYMPTOMS MAY DIFFER IN EACH INDIVIDUAL AND CHANGE OVER TIME IN THE SAME INDIVIDUAL. SYMPTOMATIC AWARENESS OF HYPOGLYCEMIA MAY BE LESS PRONOUNCED IN PATIENTS WITH LONGSTANDING DIABETES, IN PATIENTS WITH DIABETIC NERVE DISEASE, IN PATIENTS USING MEDICATIONS THAT BLOCK THE SYMPATHETIC NERVOUS SYSTEM (E.G., BETA-BLOCKERS) [SEE DRUG INTERACTIONS ], OR IN PATIENTS WHO EXPERIENCE RECURRENT HYPOGLYCEMIA.
RISK FACTORS FOR HYPOGLYCEMIA
THE RISK OF HYPOGLYCEMIA GENERALLY INCREASES WITH INTENSITY OF GLYCEMIC CONTROL. THE RISK OF HYPOGLYCEMIA AFTER AN INJECTION IS RELATED TO THE DURATION OF ACTION OF THE INSULIN [SEE CLINICAL PHARMACOLOGY ] AND, IN GENERAL, IS HIGHEST WHEN THE GLUCOSE LOWERING EFFECT OF THE INSULIN IS MAXIMAL. AS WITH ALL INSULIN PREPARATIONS, THE GLUCOSE LOWERING EFFECT TIME COURSE OF TRESIBA MAY VARY AMONG DIFFERENT INDIVIDUALS OR AT DIFFERENT TIMES IN THE SAME INDIVIDUAL AND DEPENDS ON MANY CONDITIONS, INCLUDING THE AREA OF INJECTION AS WELL AS THE INJECTION SITE BLOOD SUPPLY AND TEMPERATURE.
OTHER FACTORS WHICH MAY INCREASE THE RISK OF HYPOGLYCEMIA INCLUDE CHANGES IN MEAL PATTERN (E.G., MACRONUTRIENT CONTENT OR TIMING OF MEALS), CHANGES IN LEVEL OF PHYSICAL ACTIVITY, OR CHANGES TO CO-ADMINISTERED MEDICATION [SEE DRUG INTERACTIONS ]. PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT MAY BE AT HIGHER RISK OF HYPOGLYCEMIA [SEE USE IN SPECIFIC POPULATIONS].
RISK MITIGATION STRATEGIES FOR HYPOGLYCEMIA
PATIENTS AND CAREGIVERS MUST BE EDUCATED TO RECOGNIZE AND MANAGE HYPOGLYCEMIA. SELF-MONITORING OF BLOOD GLUCOSE PLAYS AN ESSENTIAL ROLE IN THE PREVENTION AND MANAGEMENT OF HYPOGLYCEMIA. IN PATIENTS AT HIGHER RISK FOR HYPOGLYCEMIA AND PATIENTS WHO HAVE REDUCED SYMPTOMATIC AWARENESS OF HYPOGLYCEMIA, INCREASED FREQUENCY OF BLOOD GLUCOSE MONITORING IS RECOMMENDED.
HYPOGLYCEMIA DUE TO MEDICATION ERRORS
ACCIDENTAL MIX-UPS BETWEEN BASAL INSULIN PRODUCTS AND OTHER INSULINS, PARTICULARLY RAPID-ACTING INSULINS, HAVE BEEN REPORTED. TO AVOID MEDICATION ERRORS BETWEEN TRESIBA AND OTHER INSULINS, INSTRUCT PATIENTS TO ALWAYS CHECK THE INSULIN LABEL BEFORE EACH INJECTION.
TO AVOID DOSING ERRORS AND POTENTIAL OVERDOSE, NEVER USE A SYRINGE TO REMOVE TRESIBA FROM THE TRESIBA FLEXTOUCH DISPOSABLE INSULIN PREFILLED PEN [SEE DOSAGE AND ADMINISTRATION AND HYPOGLYCEMIA].
HYPERSENSITIVITY AND ALLERGIC REACTIONS
SEVERE, LIFE-THREATENING, GENERALIZED ALLERGY , INCLUDING ANAPHYLAXIS , CAN OCCUR WITH INSULIN PRODUCTS, INCLUDING TRESIBA. IF HYPERSENSITIVITY REACTIONS OCCUR, DISCONTINUE TRESIBA; TREAT PER STANDARD OF CARE AND MONITOR UNTIL SYMPTOMS AND SIGNS RESOLVE. TRESIBA IS CONTRAINDICATED IN PATIENTS WHO HAVE HAD HYPERSENSITIVITY REACTIONS TO INSULIN DEGLUDEC OR ONE OF THE EXCIPIENTS [SEE CONTRAINDICATIONS ].
HYPOKALEMIA
ALL INSULIN PRODUCTS, INCLUDING TRESIBA, CAUSE A SHIFT IN POTASSIUM FROM THE EXTRACELLULAR TO INTRACELLULAR SPACE, POSSIBLY LEADING TO HYPOKALEMIA. UNTREATED HYPOKALEMIA MAY CAUSE RESPIRATORY PARALYSIS , VENTRICULAR ARRHYTHMIA , AND DEATH. MONITOR POTASSIUM LEVELS IN PATIENTS AT RISK FOR HYPOKALEMIA IF INDICATED (E.G., PATIENTS USING POTASSIUM-LOWERING MEDICATIONS, PATIENTS TAKING MEDICATIONS SENSITIVE TO SERUM POTASSIUM CONCENTRATIONS).
FLUID RETENTION AND CONGESTIVE HEART FAILURE WITH CONCOMITANT USE OF A PPAR GAMMA AGONIST
THIAZOLIDINEDIONES (TZDS), WHICH ARE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR )-GAMMA AGONISTS CAN CAUSE DOSE RELATED FLUID RETENTION, PARTICULARLY WHEN USED IN COMBINATION WITH INSULIN. FLUID RETENTION MAY LEAD TO OR EXACERBATE CONGESTIVE HEART FAILURE . PATIENTS TREATED WITH INSULIN, INCLUDING TRESIBA AND A PPAR-GAMMA AGONIST SHOULD BE OBSERVED FOR SIGNS AND SYMPTOMS OF CONGESTIVE HEART FAILURE . IF CONGESTIVE HEART FAILURE DEVELOPS, IT SHOULD BE MANAGED ACCORDING TO CURRENT STANDARDS OF CARE AND DISCONTINUATION OR DOSE REDUCTION OF THE PPAR-GAMMA AGONIST MUST BE CONSIDERED.
PATIENT COUNSELING INFORMATION
ADVISE THE PATIENT AND/OR CAREGIVER TO READ THE FDA-APPROVED PATIENT LABELING (PATIENT INFORMATION AND INSTRUCTIONS FOR USE ).
NEVER SHARE A TRESIBA FLEXTOUCH PEN, NEEDLE, OR SYRINGE BETWEEN PATIENTS
ADVISE PATIENTS THAT THEY SHOULD NEVER SHARE A TRESIBA FLEXTOUCH PEN DEVICE WITH ANOTHER PERSON, EVEN IF THE NEEDLE IS CHANGED. ADVISE PATIENTS USING TRESIBA VIALS NOT TO SHARE NEEDLES OR SYRINGES WITH ANOTHER PERSON. SHARING POSES A RISK FOR TRANSMISSION OF BLOOD-BORNE PATHOGENS [SEE WARNINGS AND PRECAUTIONS].
HYPERGLYCEMIA OR HYPOGLYCEMIA
INFORM PATIENTS THAT HYPOGLYCEMIA IS THE MOST COMMON ADVERSE REACTION WITH INSULIN. INFORM PATIENTS OF THE SYMPTOMS OF HYPOGLYCEMIA. INFORM PATIENTS THAT THE ABILITY TO CONCENTRATE AND REACT MAY BE IMPAIRED AS A RESULT OF HYPOGLYCEMIA. THIS MAY PRESENT A RISK IN SITUATIONS WHERE THESE ABILITIES ARE ESPECIALLY IMPORTANT, SUCH AS DRIVING OR OPERATING OTHER MACHINERY. ADVISE PATIENTS WHO HAVE FREQUENT HYPOGLYCEMIA OR REDUCED OR ABSENT WARNING SIGNS OF HYPOGLYCEMIA TO USE CAUTION WHEN DRIVING OR OPERATING MACHINERY.
ADVISE PATIENTS THAT CHANGES IN INSULIN REGIMEN CAN PREDISPOSE TO HYPER- OR HYPOGLYCEMIA. ADVISE PATIENTS THAT CHANGES IN INSULIN REGIMEN SHOULD BE MADE UNDER CLOSE MEDICAL SUPERVISION [SEE WARNINGS AND PRECAUTIONS].
MEDICATION ERRORS
INFORM PATIENTS TO ALWAYS CHECK THE INSULIN LABEL BEFORE EACH INJECTION [SEE WARNINGS AND PRECAUTIONS]. INFORM PATIENTS THAT THE DOSE COUNTER OF TRESIBA FLEXTOUCH PEN SHOWS THE NUMBER OF UNITS OF TRESIBA TO BE INJECTED. NO DOSE RE-CALCULATION IS REQUIRED [SEE DOSAGE AND ADMINISTRATION ]. INSTRUCT PATIENTS TO NEVER USE A SYRINGE TO REMOVE TRESIBA FROM THE FLEXTOUCH DISPOSABLE INSULIN PREFILLED PEN.
NONCLINICAL TOXICOLOGY
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
STANDARD 2-YEAR CARCINOGENICITY STUDIES IN ANIMALS HAVE NOT BEEN PERFORMED TO EVALUATE THE CARCINOGENIC POTENTIAL OF INSULIN DEGLUDEC. IN A 52-WEEK STUDY INCLUDING HUMAN INSULIN (NPH INSULIN) AS COMPARATOR (6.7 UNITS/KG/DAY), SPRAGUE-DAWLEY RATS WERE DOSED SUBCUTANEOUSLY WITH INSULIN DEGLUDEC AT 3.3, 6.7, AND 10 UNITS/KG/DAY, RESULTING IN 5 TIMES THE HUMAN EXPOSURE (AUC) WHEN COMPARED TO A HUMAN SUBCUTANEOUS DOSE OF 0.75 UNITS/KG/DAY. HUMAN INSULIN WAS DOSED AT 6.7 UNITS/KG/DAY. NO TREATMENT-RELATED INCREASES IN INCIDENCES OF HYPERPLASIA , BENIGN OR MALIGNANT TUMORS WERE RECORDED IN FEMALE MAMMARY GLANDS FROM RATS DOSED WITH INSULIN DEGLUDEC AND NO TREATMENT RELATED CHANGES IN THE FEMALE MAMMARY GLAND CELL PROLIFERATION WERE FOUND USING BRDU INCORPORATION. FURTHER, NO TREATMENT RELATED CHANGES IN THE OCCURRENCE OF HYPERPLASTIC OR NEOPLASTIC LESIONS WERE SEEN IN OTHER TISSUES IN ANIMALS DOSED WITH INSULIN DEGLUDEC WHEN COMPARED TO VEHICLE OR HUMAN INSULIN.
GENOTOXICITY TESTING OF INSULIN DEGLUDEC WAS NOT PERFORMED.
IN A COMBINED FERTILITY AND EMBRYO-FETAL STUDY IN MALE AND FEMALE RATS, TREATMENT WITH INSULIN DEGLUDEC UP TO 21 UNITS/KG/DAY (APPROXIMATELY 5 TIMES THE HUMAN SUBCUTANEOUS DOSE OF 0.75 UNITS/KG/DAY, BASED ON UNITS/BODY SURFACE AREA) PRIOR TO MATING AND IN FEMALE RATS DURING GESTATION HAD NO EFFECT ON MATING PERFORMANCE AND FERTILITY.
USE IN SPECIFIC POPULATIONS
PREGNANCY
RISK SUMMARY
THERE ARE NO AVAILABLE DATA WITH TRESIBA OR INSULIN DEGLUDEC IN PREGNANT WOMEN TO INFORM A DRUG-ASSOCIATED RISK FOR MAJOR BIRTH DEFECTS AND MISCARRIAGE . THERE ARE RISKS TO THE MOTHER AND FETUS ASSOCIATED WITH POORLY CONTROLLED DIABETES IN PREGNANCY [SEE CLINICAL CONSIDERATIONS].
RATS AND RABBITS WERE EXPOSED TO INSULIN DEGLUDEC IN ANIMAL REPRODUCTION STUDIES DURING ORGANOGENESIS. PRE-AND POST-IMPLANTATION LOSSES AND VISCERAL /SKELETAL ABNORMALITIES WERE OBSERVED IN RATS AT DOSES 5 TIMES (RAT) AND AT 10 TIMES (RABBIT) THE HUMAN EXPOSURE AT A DOSE OF 0.75 U/KG/DAY. THESE EFFECTS WERE SIMILAR TO THOSE OBSERVED IN RATS ADMINISTERED HUMAN INSULIN (NPH) [SEE DATA].
THE ESTIMATED BACKGROUND RISK OF MAJOR BIRTH DEFECTS IS 6-10% IN WOMEN WITH PRE-GESTATIONAL DIABETES WITH AN HBA1C >7 AND HAS BEEN REPORTED TO BE AS HIGH AS 20-25% IN WOMEN WITH AN HBA1C >10. THE ESTIMATED BACKGROUND RISK OF MISCARRIAGE FOR THE INDICATED POPULATION IS UNKNOWN. IN THE U.S. GENERAL POPULATION, THE ESTIMATED BACKGROUND RISK OF MAJOR BIRTH DEFECTS AND MISCARRIAGE IN CLINICALLY RECOGNIZED PREGNANCIES IS 2-4% AND 15-20%, RESPECTIVELY.
CLINICAL CONSIDERATIONS
DISEASE-ASSOCIATED MATERNAL AND/OR EMBRYO/FETAL RISK
POORLY CONTROLLED DIABETES IN PREGNANCY INCREASES THE MATERNAL RISK FOR DIABETIC KETOACIDOSIS , PRE-ECLAMPSIA , SPONTANEOUS ABORTIONS, PRETERM DELIVERY, STILLBIRTH AND DELIVERY COMPLICATIONS. POORLY CONTROLLED DIABETES INCREASES THE FETAL RISK FOR MAJOR BIRTH DEFECTS, STILL BIRTH, AND MACROSOMIA RELATED MORBIDITY.
DATA
ANIMAL DATA
INSULIN DEGLUDEC WAS INVESTIGATED IN STUDIES COVERING FERTILITY, EMBRYO-FETAL DEVELOPMENT AND PRE-AND POSTNATAL DEVELOPMENT IN RATS AND DURING THE PERIOD OF EMBRYO-FETAL DEVELOPMENT IN RABBITS. HUMAN INSULIN (NPH INSULIN) WAS INCLUDED AS COMPARATOR. IN THESE STUDIES INSULIN DEGLUDEC CAUSED PRE-AND POST-IMPLANTATION LOSSES AND VISCERAL/SKELETAL ABNORMALITIES WHEN GIVEN SUBCUTANEOUSLY AT UP TO 21 U/KG/DAY IN RATS AND 3.3 U/KG/DAY IN RABBITS, RESULTING IN 5 TIMES (RAT) AND 10 TIMES (RABBIT) THE HUMAN EXPOSURE (AUC) AT A HUMAN SUBCUTANEOUS DOSE OF 0.75 U/KG/DAY. OVERALL, THE EFFECTS OF INSULIN DEGLUDEC WERE SIMILAR TO THOSE OBSERVED WITH HUMAN INSULIN, WHICH WERE PROBABLY SECONDARY TO MATERNAL HYPOGLYCEMIA.
LACTATION
RISK SUMMARY
THERE ARE NO DATA ON THE PRESENCE OF INSULIN DEGLUDEC IN HUMAN MILK, THE EFFECTS ON THE BREASTFED INFANT, OR THE EFFECTS ON MILK PRODUCTION. INSULIN DEGLUDEC IS PRESENT IN RAT MILK [SEE DATA]. THE DEVELOPMENTAL AND HEALTH BENEFITS OF BREASTFEEDING SHOULD BE CONSIDERED ALONG WITH THE MOTHER'S CLINICAL NEED FOR TRESIBA AND ANY POTENTIAL ADVERSE EFFECTS ON THE BREASTFED INFANT FROM TRESIBA OR FROM THE UNDERLYING MATERNAL CONDITION.
DATA
IN LACTATING RATS, INSULIN DEGLUDEC WAS PRESENT IN MILK AT A CONCENTRATION LOWER THAN THAT IN PLASMA.
PEDIATRIC USE
THE SAFETY AND EFFECTIVENESS OF TRESIBA TO IMPROVE GLYCEMIC CONTROL IN TYPE 1 AND TYPE 2 DIABETES MELLITUS HAVE BEEN ESTABLISHED IN PEDIATRIC PATIENTS 1 YEAR OF AGE AND OLDER. THE SAFETY AND EFFECTIVENESS OF TRESIBA HAVE NOT BEEN ESTABLISHED IN PEDIATRIC PATIENTS LESS THAN 1 YEAR OLD.
THE USE OF TRESIBA IN PEDIATRIC PATIENTS 1 YEAR OF AGE AND OLDER WITH TYPE 1 AND TYPE 2 DIABETES MELLITUS IS SUPPORTED BY EVIDENCE FROM AN ADEQUATE AND WELL-CONTROLLED STUDY AND A PHARMACOKINETIC STUDY (STUDIES INCLUDED PEDIATRIC PATIENTS 1 YEAR OF AGE AND OLDER WITH TYPE 1 DIABETES MELLITUS) [SEE CLINICAL PHARMACOLOGY AND CLINICAL STUDIES ]. THE USE OF TRESIBA IN PEDIATRIC PATIENTS 1 YEAR OF AGE AND OLDER WITH TYPE 2 DIABETES MELLITUS IS ALSO SUPPORTED BY EVIDENCE FROM ADEQUATE AND WELL-CONTROLLED STUDIES IN ADULTS WITH TYPE 2 DIABETES MELLITUS [SEE CLINICAL STUDIES].
IN PEDIATRIC PATIENTS 1 YEAR OF AGE AND OLDER ALREADY ON INSULIN THERAPY, START TRESIBA AT A REDUCED DOSE TO MINIMIZE THE RISK OF HYPOGLYCEMIA [SEE DOSAGE AND ADMINISTRATION ].
GERIATRIC USE
IN CONTROLLED CLINICAL STUDIES [SEE CLINICAL STUDIES ] A TOTAL OF 77 (7%) OF THE 1102 TRESIBA -TREATED PATIENTS WITH TYPE 1 DIABETES WERE 65 YEARS OR OLDER AND 9 (1%) WERE 75 YEARS OR OLDER. A TOTAL OF 670 (25%) OF THE 2713 TRESIBA-TREATED PATIENTS WITH TYPE 2 DIABETES WERE 65 YEARS OR OLDER AND 80 (3%) WERE 75 YEARS OR OLDER. DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE NOT SUGGESTED IN SUBGROUP ANALYSES COMPARING SUBJECTS OLDER THAN 65 YEARS TO YOUNGER SUBJECTS.
IN THE SAFETY OUTCOMES TRIAL (DEVOTE), A TOTAL OF 1983 (52%) OF THE 3818 TRESIBA-TREATED PATIENTS WITH TYPE 2 DIABETES WERE 65 YEARS OR OLDER AND 381 (10%) WERE 75 YEARS OR OLDER. DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE NOT OBSERVED IN THESE SUBGROUP ANALYSES.
NEVERTHELESS, GREATER CAUTION SHOULD BE EXERCISED WHEN TRESIBA IS ADMINISTERED TO GERIATRIC PATIENTS SINCE GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS TO THE EFFECTS OF TRESIBA CANNOT BE RULED OUT. THE INITIAL DOSING, DOSE INCREMENTS, AND MAINTENANCE DOSAGE SHOULD BE CONSERVATIVE TO AVOID HYPOGLYCEMIA. HYPOGLYCEMIA MAY BE MORE DIFFICULT TO RECOGNIZE IN THE ELDERLY.
RENAL IMPAIRMENT
IN CLINICAL STUDIES [SEE CLINICAL STUDIES ] A TOTAL OF 75 (7%) OF THE 1102 TRESIBA-TREATED PATIENTS WITH TYPE 1 DIABETES HAD AN EGFR LESS THAN 60 ML/MIN/1.73 M² AND 1 (0.1%) HAD AN EGFR LESS THAN 30 ML/MIN/1.73 M². A TOTAL OF 250 (9%) OF THE 2713 TRESIBA-TREATED PATIENTS WITH TYPE 2 DIABETES HAD AN EGFR LESS THAN 60 ML/MIN/1.73 M² AND NO SUBJECTS HAD AN EGFR LESS THAN 30 ML/MIN/1.73 M².
IN THE SAFETY OUTCOMES TRIAL (DEVOTE), A TOTAL OF 1429 (37.4%) OF THE 3818 TRESIBA-TREATED PATIENTS WITH TYPE 2 DIABETES HAD AN EGFR LESS THAN 60 ML/MIN/1.73 M², AND 108 (2.8%) SUBJECTS HAD AN EGFR LESS THAN 30 ML/MIN/1.73 M². DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE NOT OBSERVED IN THE SUBGROUP ANALYSES.
NO CLINICALLY RELEVANT DIFFERENCE IN THE PHARMACOKINETICS OF TRESIBA WAS IDENTIFIED IN A STUDY COMPARING HEALTHY SUBJECTS AND SUBJECTS WITH RENAL IMPAIRMENT INCLUDING SUBJECTS WITH END STAGE RENAL DISEASE [SEE CLINICAL PHARMACOLOGY ]. HOWEVER, AS WITH ALL INSULIN PRODUCTS, GLUCOSE MONITORING SHOULD BE INTENSIFIED AND THE TRESIBA DOSAGE ADJUSTED ON AN INDIVIDUAL BASIS IN PATIENTS WITH RENAL IMPAIRMENT.
HEPATIC IMPAIRMENT
NO DIFFERENCE IN THE PHARMACOKINETICS OF TRESIBA WAS IDENTIFIED IN A STUDY COMPARING HEALTHY SUBJECTS AND SUBJECTS WITH HEPATIC IMPAIRMENT (MILD, MODERATE, AND SEVERE HEPATIC IMPAIRMENT) [SEE CLINICAL PHARMACOLOGY ]. HOWEVER, AS WITH ALL INSULIN PRODUCTS, GLUCOSE MONITORING SHOULD BE INTENSIFIED AND THE TRESIBA DOSAGE ADJUSTED ON AN INDIVIDUAL BASIS IN PATIENTS WITH HEPATIC IMPAIRMENT.
OVERDOSAGE & CONTRAINDICATIONS
OVERDOSE
AN EXCESS OF INSULIN RELATIVE TO FOOD INTAKE, ENERGY EXPENDITURE, OR BOTH MAY LEAD TO SEVERE AND SOMETIMES PROLONGED AND LIFE-THREATENING HYPOGLYCEMIA AND HYPOKALEMIA [SEE WARNINGS AND PRECAUTIONS ]. MILD EPISODES OF HYPOGLYCEMIA USUALLY CAN BE TREATED WITH ORAL GLUCOSE. ADJUSTMENTS IN DRUG DOSAGE, MEAL PATTERNS, OR EXERCISE MAY BE NEEDED. MORE SEVERE EPISODES OF HYPOGLYCEMIA WITH COMA, SEIZURE , OR NEUROLOGIC IMPAIRMENT MAY BE TREATED WITH INTRAMUSCULAR /SUBCUTANEOUS GLUCAGON OR CONCENTRATED INTRAVENOUS GLUCOSE. AFTER APPARENT CLINICAL RECOVERY FROM HYPOGLYCEMIA, CONTINUED OBSERVATION AND ADDITIONAL CARBOHYDRATE INTAKE MAY BE NECESSARY TO AVOID REOCCURRENCE OF HYPOGLYCEMIA. HYPOKALEMIA MUST BE CORRECTED APPROPRIATELY.
CONTRAINDICATIONS
TRESIBA IS CONTRAINDICATED:
· DURING EPISODES OF HYPOGLYCEMIA [SEE WARNINGS AND PRECAUTIONS ].
· IN PATIENTS WITH HYPERSENSITIVITY TO TRESIBA OR ONE OF ITS EXCIPIENTS [SEE WARNINGS AND PRECAUTIONS ].
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
THE PRIMARY ACTIVITY OF INSULIN, INCLUDING TRESIBA, IS REGULATION OF GLUCOSE METABOLISM . INSULIN AND ITS ANALOGS LOWER BLOOD GLUCOSE BY STIMULATING PERIPHERAL GLUCOSE UPTAKE, ESPECIALLY BY SKELETAL MUSCLE AND FAT, AND BY INHIBITING HEPATIC GLUCOSE PRODUCTION. INSULIN ALSO INHIBITS LIPOLYSIS AND PROTEOLYSIS, AND ENHANCES PROTEIN SYNTHESIS. TRESIBA FORMS MULTI-HEXAMERS WHEN INJECTED INTO THE SUBCUTANEOUS TISSUE RESULTING IN A SUBCUTANEOUS INSULIN DEGLUDEC DEPOT. THE PROTRACTED TIME ACTION PROFILE OF TRESIBA IS PREDOMINANTLY DUE TO DELAYED ABSORPTION OF INSULIN DEGLUDEC FROM THE SUBCUTANEOUS TISSUE TO THE SYSTEMIC CIRCULATION AND TO A LESSER EXTENT DUE TO BINDING OF INSULIN-DEGLUDEC TO CIRCULATING ALBUMIN .
PHARMACODYNAMICS
THE GLUCOSE-LOWERING EFFECT OF TRESIBA AFTER 8 DAYS OF ONCE-DAILY DOSING WAS MEASURED IN A EUGLYCEMIC GLUCOSE CLAMP STUDY ENROLLING 21 PATIENTS WITH TYPE 1 DIABETES. FIGURE 2 SHOWS THE PHARMACODYNAMIC EFFECT OF TRESIBA OVER TIME FOLLOWING 8 ONCE-DAILY SUBCUTANEOUS INJECTIONS OF 0.4 U/KG OF TRESIBA IN PATIENTS WITH TYPE 1 DIABETES.
THE MEAN MAXIMUM GLUCOSE LOWERING EFFECT (GIRMAX) OF A 0.4 UNITS/KG DOSE OF TRESIBA WAS 2.0 MG/KG/MIN, WHICH WAS OBSERVED AT A MEDIAN OF 12 HOURS POST-DOSE. THE GLUCOSE LOWERING EFFECT OF TRESIBA LASTED AT LEAST 42 HOURS AFTER THE LAST OF 8 ONCE-DAILY INJECTIONS.
IN PATIENTS WITH TYPE 1 DIABETES MELLITUS, THE STEADY-STATE, WITHIN SUBJECTS, DAY-TO-DAY VARIABILITY IN TOTAL GLUCOSE LOWERING EFFECT WAS 20% WITH TRESIBA (WITHIN-SUBJECT COEFFICIENT OF VARIATION FOR AUCGIR,?,SS).
THE TOTAL GLUCOSE-LOWERING EFFECT OF TRESIBA OVER 24 HOURS MEASURED IN A EUGLYCEMIC CLAMP STUDY AFTER 8 DAYS OF ONCE-DAILY ADMINISTRATION IN PATIENTS WITH TYPE 1 DIABETES INCREASES APPROXIMATELY IN PROPORTION TO THE DOSE FOR DOSES BETWEEN 0.4 UNITS/KG TO 0.8 UNITS/KG.
THE TOTAL GLUCOSE-LOWERING EFFECT OF 0.4 UNITS/KG OF TRESIBA U-100 AND 0.4 UNITS/KG OF TRESIBA U-200, ADMINISTERED AT THE SAME DOSE, AND ASSESSED OVER 24 HOURS IN A EUGLYCEMIC CLAMP STUDY AFTER 8 DAYS OF ONCE-DAILY INJECTION WAS COMPARABLE.
PHARMACOKINETICS
ABSORPTION
IN PATIENTS WITH TYPE 1 DIABETES, AFTER 8 DAYS OF ONCE DAILY SUBCUTANEOUS DOSING WITH 0.4 UNITS/KG OF TRESIBA, MAXIMUM DEGLUDEC CONCENTRATIONS OF 4472 PMOL/L WERE ATTAINED AT A MEDIAN OF 9 HOURS (TMAX). AFTER THE FIRST DOSE OF TRESIBA, MEDIAN ONSET OF APPEARANCE WAS AROUND ONE HOUR.
TOTAL INSULIN DEGLUDEC CONCENTRATION (I.E., EXPOSURE) INCREASED IN A DOSE PROPORTIONAL MANNER AFTER SUBCUTANEOUS ADMINISTRATION OF 0.4 UNITS/KG TO 0.8 UNITS/KG TRESIBA. TOTAL AND MAXIMUM INSULIN DEGLUDEC EXPOSURE AT STEADY STATE ARE COMPARABLE BETWEEN TRESIBA U-100 AND TRESIBA U-200 WHEN EACH IS ADMINISTERED AT THE SAME UNITS/KG DOSE.
INSULIN DEGLUDEC CONCENTRATION REACHED STEADY STATE LEVELS AFTER 3-4 DAYS OF TRESIBA ADMINISTRATION [SEE DOSAGE AND ADMINISTRATION ].
DISTRIBUTION
THE AFFINITY OF INSULIN DEGLUDEC TO SERUM ALBUMIN CORRESPONDS TO A PLASMA PROTEIN BINDING OF >99% IN HUMAN PLASMA. THE RESULTS OF THE IN VITRO PROTEIN BINDING STUDIES DEMONSTRATE THAT THERE IS NO CLINICALLY RELEVANT INTERACTION BETWEEN INSULIN DEGLUDEC AND OTHER PROTEIN BOUND DRUGS.
ELIMINATION
THE HALF-LIFE AFTER SUBCUTANEOUS ADMINISTRATION IS DETERMINED PRIMARILY BY THE RATE OF ABSORPTION FROM THE SUBCUTANEOUS TISSUE. ON AVERAGE, THE HALF-LIFE AT STEADY STATE IS APPROXIMATELY 25 HOURS INDEPENDENT OF DOSE. DEGRADATION OF TRESIBA IS SIMILAR TO THAT OF INSULIN HUMAN; ALL METABOLITES FORMED ARE INACTIVE. THE MEAN APPARENT CLEARANCE OF INSULIN DEGLUDEC IS 0.03 L/KG (2.1 L/H IN 70 KG INDIVIDUAL) AFTER SINGLE SUBCUTANEOUS DOSE OF 0.4 UNITS/KG.
SPECIFIC POPULATIONS
PEDIATRICS
POPULATION PHARMACOKINETIC ANALYSIS WAS CONDUCTED FOR TRESIBA USING DATA FROM 199 PEDIATRIC SUBJECTS (1 TO <18 YEARS OF AGE) WITH TYPE 1 DIABETES. BODY WEIGHT WAS A SIGNIFICANT COVARIATE AFFECTING THE CLEARANCE OF TRESIBA. AFTER ADJUSTING FOR BODY WEIGHT, THE TOTAL EXPOSURE OF TRESIBA AT STEADY STATE WAS INDEPENDENT OF AGE.
GERIATRICS
PHARMACOKINETIC AND PHARMACODYNAMIC RESPONSE OF TRESIBA WAS COMPARED IN 13 YOUNGER ADULT (18-35 YEARS) AND 14 GERIATRIC (?65 YEARS) SUBJECTS WITH TYPE 1 DIABETES FOLLOWING TWO 6-DAY PERIODS OF ONCE-DAILY SUBCUTANEOUS DOSING WITH 0.4 UNITS/KG DOSE OF TRESIBA OR INSULIN GLARGINE. ON AVERAGE, THE PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF TRESIBA AT STEADY-STATE WERE SIMILAR IN YOUNGER ADULT AND GERIATRIC SUBJECTS, ALBEIT WITH GREATER BETWEEN SUBJECT VARIABILITY AMONG THE GERIATRIC SUBJECTS.
GENDER
THE EFFECT OF GENDER ON THE PHARMACOKINETICS OF TRESIBA WAS EXAMINED IN AN ACROSS-TRIAL ANALYSIS OF THE PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES CONDUCTED USING UNIT/KG DOSES OF TRESIBA. OVERALL, THERE WERE NO CLINICALLY RELEVANT DIFFERENCES IN THE PHARMACOKINETIC PROPERTIES OF INSULIN DEGLUDEC BETWEEN FEMALE AND MALE SUBJECTS.
OBESITY
THE EFFECT OF BMI ON THE PHARMACOKINETICS OF TRESIBA WAS EXPLORED IN A CROSS-TRIAL ANALYSIS OF PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES CONDUCTED USING UNIT/KG DOSES OF TRESIBA. FOR SUBJECTS WITH TYPE 1 DIABETES, NO RELATIONSHIP BETWEEN EXPOSURE OF TRESIBA AND BMI WAS OBSERVED. FOR SUBJECTS WITH TYPE 1 AND TYPE 2 DIABETES A TREND FOR DECREASE IN GLUCOSE-LOWERING EFFECT OF TRESIBA WITH INCREASING BMI WAS OBSERVED.
RACE AND ETHNICITY
TRESIBA HAS BEEN STUDIED IN A PHARMACOKINETIC AND PHARMACODYNAMIC STUDY IN BLACK OR AFRICAN AMERICAN SUBJECTS NOT OF HISPANIC OR LATINO ORIGIN (N=18), WHITE SUBJECTS OF HISPANIC OR LATINO ORIGIN (N=22) AND WHITE SUBJECTS NOT OF HISPANIC OR LATINO ORIGIN (N=23) WITH TYPE 2 DIABETES MELLITUS CONDUCTED USING UNIT/KG DOSES OF TRESIBA. THERE WERE NO STATISTICALLY SIGNIFICANT DIFFERENCES IN THE PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES OF TRESIBA BETWEEN THE RACIAL AND ETHNIC GROUPS INVESTIGATED.
PREGNANCY
THE EFFECT OF PREGNANCY ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF TRESIBA HAS NOT BEEN STUDIED [SEE USE IN SPECIFIC POPULATIONS ].
RENAL IMPAIRMENT
TRESIBA PHARMACOKINETICS WAS STUDIED IN 32 SUBJECTS (N=4-8/GROUP) WITH NORMAL OR IMPAIRED RENAL FUNCTION/END-STAGE RENAL DISEASE FOLLOWING ADMINISTRATION OF A SINGLE SUBCUTANEOUS DOSE (0.4 UNITS/KG) OF TRESIBA. RENAL FUNCTION WAS DEFINED USING CREATININE CLEARANCE (CLCR) AS FOLLOWS: ?90 ML/MIN (NORMAL), 6089 ML/MIN (MILD), 30-59 ML/MIN (MODERATE) AND <30 ML/MIN (SEVERE). SUBJECTS REQUIRING DIALYSIS WERE CLASSIFIED AS HAVING END-STAGE RENAL DISEASE (ESRD ). TOTAL (AUCIDEG,0-120H,SD) AND PEAK EXPOSURE OF TRESIBA WERE ON AVERAGE ABOUT 10-25% AND 13-27% HIGHER, RESPECTIVELY IN SUBJECTS WITH MILD TO SEVERE RENAL IMPAIRMENT EXCEPT SUBJECTS WITH ESRD WHO SHOWED SIMILAR EXPOSURE AS COMPARED TO SUBJECTS WITH NORMAL RENAL FUNCTION. NO SYSTEMATIC TREND WAS NOTED FOR THIS INCREASE IN EXPOSURE ACROSS DIFFERENT RENAL IMPAIRMENT SUBGROUPS. HEMODIALYSIS DID NOT AFFECT CLEARANCE OF TRESIBA (CL/FIDEG,SD) IN SUBJECTS WITH ESRD [SEE USE IN SPECIFIC POPULATIONS ].
HEPATIC IMPAIRMENT
TRESIBA HAS BEEN STUDIED IN A PHARMACOKINETIC STUDY IN 24 SUBJECTS (N=6/GROUP) WITH NORMAL OR IMPAIRED HEPATIC FUNCTION (MILD, MODERATE, AND SEVERE HEPATIC IMPAIRMENT) FOLLOWING ADMINISTRATION OF A SINGLE SUBCUTANEOUS DOSE (0.4 UNITS/KG) OF TRESIBA. HEPATIC FUNCTION WAS DEFINED USING CHILD-PUGH SCORES RANGING FROM 5 (MILD HEPATIC IMPAIRMENT) TO 15 (SEVERE HEPATIC IMPAIRMENT). NO DIFFERENCES IN THE PHARMACOKINETICS OF TRESIBA WERE IDENTIFIED BETWEEN HEALTHY SUBJECTS AND SUBJECTS WITH HEPATIC IMPAIRMENT [SEE USE IN SPECIFIC POPULATIONS ].
CLINICAL STUDIES
THE EFFICACY OF TRESIBA ADMINISTERED ONCE-DAILY EITHER AT THE SAME TIME EACH DAY OR AT ANY TIME EACH DAY IN PATIENTS WITH TYPE 1 DIABETES AND USED IN COMBINATION WITH A MEALTIME INSULIN WAS EVALUATED IN THREE RANDOMIZED, OPEN-LABEL, TREAT-TO-TARGET, ACTIVE-CONTROLLED TRIALS IN ADULTS AND ONE RANDOMIZED, OPEN-LABEL, TREAT-TO-TARGET, ACTIVE-CONTROLLED TRIAL IN PEDIATRIC PATIENTS 1 YEAR OF AGE AND OLDER. THE EFFICACY OF TRESIBA ADMINISTERED ONCE-DAILY EITHER AT THE SAME TIME EACH DAY OR AT ANY TIME EACH DAY IN ADULT PATIENTS WITH TYPE 2 DIABETES AND USED IN COMBINATION WITH A MEALTIME INSULIN OR IN COMBINATION WITH COMMON ORAL ANTI-DIABETIC AGENTS WAS EVALUATED IN SIX RANDOMIZED, OPEN-LABEL, TREAT-TO-TARGET ACTIVE-CONTROLLED TRIALS.
ADULT PATIENTS TREATED WITH TRESIBA ACHIEVED LEVELS OF GLYCEMIC CONTROL SIMILAR TO THOSE ACHIEVED WITH LANTUS (INSULIN GLARGINE 100 UNITS/ML) AND LEVEMIR (INSULIN DETEMIR) AND ACHIEVED STATISTICALLY SIGNIFICANT IMPROVEMENTS COMPARED TO SITAGLIPTIN.