NINTEDANIB
OFEV CAPSULES
DESCRIPTION
OFEV CAPSULES CONTAIN NINTEDANIB, A KINASE INHIBITOR [SEE MECHANISM OF ACTION ]. NINTEDANIB IS PRESENTED AS THE ETHANESULFONATE SALT (ESYLATE), WITH THE CHEMICAL NAME 1H-INDOLE-6-CARBOXYLIC ACID, 2,3- DIHYDRO-3-[[[4-[METHYL[(4-METHYL-1-PIPERAZINYL)ACETYL]AMINO]PHENYL]AMINO]PHENYLMETHYLENE]-2-OXO-,METHYL ESTER, (3Z)-, ETHANESULFONATE (1:1
OFEV CAPSULES FOR ORAL ADMINISTRATION ARE AVAILABLE IN 2 DOSE STRENGTHS CONTAINING 100 MG OR 150 MG OF NINTEDANIB (EQUIVALENT TO 120.40 MG OR 180.60 MG NINTEDANIB ETHANESULFONATE, RESPECTIVELY). THE INACTIVE INGREDIENTS OF OFEV ARE THE FOLLOWING: FILL MATERIAL: TRIGLYCERIDES, HARD FAT, LECITHIN. CAPSULE SHELL: GELATIN, GLYCEROL, TITANIUM DIOXIDE, RED FERRIC OXIDE, YELLOW FERRIC OXIDE, BLACK INK.
INDICATIONS & DOSAGE
INDICATIONS
IDIOPATHIC PULMONARY FIBROSIS
OFEV IS INDICATED FOR THE TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS (IPF).
CHRONIC FIBROSING INTERSTITIAL LUNG DISEASES WITH A PROGRESSIVE PHENOTYPE
OFEV IS INDICATED FOR THE TREATMENT OF CHRONIC FIBROSING INTERSTITIAL LUNG DISEASES (ILDS) WITH A PROGRESSIVE PHENOTYPE [SEE CLINICAL STUDIES].
SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE
OFEV IS INDICATED TO SLOW THE RATE OF DECLINE IN PULMONARY FUNCTION IN PATIENTS WITH SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (SSC-ILD).
DOSAGE AND ADMINISTRATION
TESTING PRIOR TO OFEV ADMINISTRATION
CONDUCT LIVER FUNCTION TESTS IN ALL PATIENTS AND A PREGNANCY TEST IN FEMALES OF REPRODUCTIVE POTENTIAL PRIOR TO INITIATING TREATMENT WITH OFEV [SEE WARNINGS AND PRECAUTIONS].
RECOMMENDED DOSAGE
THE RECOMMENDED DOSAGE OF OFEV IS 150 MG TWICE DAILY ADMINISTERED APPROXIMATELY 12 HOURS APART.
OFEV CAPSULES SHOULD BE TAKEN WITH FOOD [SEE CLINICAL PHARMACOLOGY] AND SWALLOWED WHOLE WITH LIQUID. OFEV CAPSULES SHOULD NOT BE CHEWED OR CRUSHED BECAUSE OF A BITTER TASTE. THE EFFECT OF CHEWING OR CRUSHING OF THE CAPSULE ON THE PHARMACOKINETICS OF NINTEDANIB IS NOT KNOWN.
IF A DOSE OF OFEV IS MISSED, THE NEXT DOSE SHOULD BE TAKEN AT THE NEXT SCHEDULED TIME. ADVISE THE PATIENT TO NOT MAKE UP FOR A MISSED DOSE. DO NOT EXCEED THE RECOMMENDED MAXIMUM DAILY DOSAGE OF 300 MG.
IN PATIENTS WITH MILD HEPATIC IMPAIRMENT (CHILD PUGH A), THE RECOMMENDED DOSAGE OF OFEV IS 100 MG TWICE DAILY APPROXIMATELY 12 HOURS APART TAKEN WITH FOOD.
DOSAGE MODIFICATION DUE TO ADVERSE REACTIONS
IN ADDITION TO SYMPTOMATIC TREATMENT, IF APPLICABLE, THE MANAGEMENT OF ADVERSE REACTIONS OF OFEV MAY REQUIRE DOSE REDUCTION OR TEMPORARY INTERRUPTION UNTIL THE SPECIFIC ADVERSE REACTION RESOLVES TO LEVELS THAT ALLOW CONTINUATION OF THERAPY. OFEV TREATMENT MAY BE RESUMED AT THE FULL DOSAGE (150 MG TWICE DAILY), OR AT THE REDUCED DOSAGE (100 MG TWICE DAILY), WHICH SUBSEQUENTLY MAY BE INCREASED TO THE FULL DOSAGE. IF A PATIENT DOES NOT TOLERATE 100 MG TWICE DAILY, DISCONTINUE TREATMENT WITH OFEV [SEE WARNINGS AND PRECAUTIONS AND ADVERSE REACTIONS].
DOSE MODIFICATIONS OR INTERRUPTIONS MAY BE NECESSARY FOR LIVER ENZYME ELEVATIONS. CONDUCT LIVER FUNCTION TESTS (ASPARTATE AMINOTRANSFERASE (AST), ALANINE AMINOTRANSFERASE (ALT), AND BILIRUBIN) PRIOR TO INITIATION OF TREATMENT WITH OFEV, AT REGULAR INTERVALS DURING THE FIRST THREE MONTHS OF TREATMENT, AND PERIODICALLY THEREAFTER OR AS CLINICALLY INDICATED. MEASURE LIVER TESTS PROMPTLY IN PATIENTS WHO REPORT SYMPTOMS THAT MAY INDICATE LIVER INJURY, INCLUDING FATIGUE, ANOREXIA, RIGHT UPPER ABDOMINAL DISCOMFORT, DARK URINE OR JAUNDICE. DISCONTINUE OFEV IN PATIENTS WITH AST OR ALT GREATER THAN 3 TIMES THE UPPER LIMIT OF NORMAL (ULN) WITH SIGNS OR SYMPTOMS OF LIVER INJURY AND FOR AST OR ALT ELEVATIONS GREATER THAN 5 TIMES THE UPPER LIMIT OF NORMAL. FOR AST OR ALT GREATER THAN 3 TIMES TO LESS THAN 5 TIMES THE ULN WITHOUT SIGNS OF LIVER DAMAGE, INTERRUPT TREATMENT OR REDUCE OFEV TO 100 MG TWICE DAILY. ONCE LIVER ENZYMES HAVE RETURNED TO BASELINE VALUES, TREATMENT WITH OFEV MAY BE REINTRODUCED AT A REDUCED DOSAGE (100 MG TWICE DAILY), WHICH SUBSEQUENTLY MAY BE INCREASED TO THE FULL DOSAGE (150 MG TWICE DAILY) [SEE WARNINGS AND PRECAUTIONS AND ADVERSE REACTIONS ].
IN PATIENTS WITH MILD HEPATIC IMPAIRMENT (CHILD PUGH A), CONSIDER TREATMENT INTERRUPTION, OR DISCONTINUATION FOR MANAGEMENT OF ADVERSE REACTIONS.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
150 MG CAPSULES: BROWN, OPAQUE, OBLONG, SOFT CAPSULES IMPRINTED IN BLACK WITH THE BOEHRINGER INGELHEIM COMPANY SYMBOL AND "150".
100 MG CAPSULES: PEACH, OPAQUE, OBLONG, SOFT CAPSULES IMPRINTED IN BLACK WITH THE BOEHRINGER INGELHEIM COMPANY SYMBOL AND "100".
STORAGE AND HANDLING
150 MG: BROWN, OPAQUE, OBLONG, SOFT CAPSULES IMPRINTED IN BLACK WITH THE BOEHRINGER INGELHEIM COMPANY SYMBOL AND "150". THEY ARE PACKAGED IN HDPE BOTTLES WITH A CHILD-RESISTANT CLOSURE, AVAILABLE AS FOLLOWS: BOTTLES OF 60 - NDC: 0597-0145-60
100 MG: PEACH, OPAQUE, OBLONG, SOFT CAPSULES IMPRINTED IN BLACK WITH THE BOEHRINGER INGELHEIM COMPANY SYMBOL AND "100". THEY ARE PACKAGED IN HDPE BOTTLES WITH A CHILD-RESISTANT CLOSURE, AVAILABLE AS FOLLOWS: BOTTLES OF 60 - NDC: 0597-0143-60
STORAGE
STORE AT 25掳C (77掳F); EXCURSIONS PERMITTED TO 15掳 TO 30掳C (59掳 TO 86掳F) [SEE USP CONTROLLED ROOM TEMPERATURE]. PROTECT FROM EXPOSURE TO HIGH HUMIDITY AND AVOID EXCESSIVE HEAT. IF REPACKAGED, USE USP TIGHT CONTAINER. KEEP OUT OF REACH OF CHILDREN.
DISTRIBUTED BY: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. RIDGEFIELD, CT 06877 USA. REVISED: MAR 2020
SIDE EFFECTS
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE DISCUSSED IN GREATER DETAIL IN OTHER SECTIONS OF THE LABELING:
路 ELEVATED LIVER ENZYMES AND DRUG-INDUCED LIVER INJURY [SEE WARNINGS AND PRECAUTIONS]
路 GASTROINTESTINAL DISORDERS [SEE WARNINGS AND PRECAUTIONS]
路 EMBRYO-FETAL TOXICITY [SEE WARNINGS AND PRECAUTIONS]
路 ARTERIAL THROMBOEMBOLIC EVENTS [SEE WARNINGS AND PRECAUTIONS]
路 RISK OF BLEEDING [SEE WARNINGS AND PRECAUTIONS]
路 GASTROINTESTINAL PERFORATION [SEE WARNINGS AND PRECAUTIONS]
CLINICAL TRIALS 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 OFEV WAS EVALUATED IN OVER 1000 IPF PATIENTS, 332 PATIENTS WITH CHRONIC FIBROSING ILDS WITH A PROGRESSIVE PHENOTYPE, AND OVER 280 PATIENTS WITH SSC-ILD. OVER 200 IPF PATIENTS WERE EXPOSED TO OFEV FOR MORE THAN 2 YEARS IN CLINICAL TRIALS.
IDIOPATHIC PULMONARY FIBROSIS
OFEV WAS STUDIED IN THREE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 52-WEEK TRIALS. IN THE PHASE 2 (STUDY 1) AND PHASE 3 (STUDY 2 AND STUDY 3) TRIALS, 723 PATIENTS WITH IPF RECEIVED OFEV 150 MG TWICE DAILY AND 508 PATIENTS RECEIVED PLACEBO. THE MEDIAN DURATION OF EXPOSURE WAS 10 MONTHS FOR PATIENTS TREATED WITH OFEV AND 11 MONTHS FOR PATIENTS TREATED WITH PLACEBO. SUBJECTS RANGED IN AGE FROM 42 TO 89 YEARS (MEDIAN AGE OF 67 YEARS). MOST PATIENTS WERE MALE (79%) AND CAUCASIAN (60%).
THE MOST FREQUENT SERIOUS ADVERSE REACTIONS REPORTED IN PATIENTS TREATED WITH OFEV, MORE THAN PLACEBO, WERE BRONCHITIS (1.2% VS. 0.8%) AND MYOCARDIAL INFARCTION (1.5% VS. 0.4%). THE MOST COMMON ADVERSE EVENTS LEADING TO DEATH IN PATIENTS TREATED WITH OFEV, MORE THAN PLACEBO, WERE PNEUMONIA (0.7% VS. 0.6%), LUNG NEOPLASM MALIGNANT (0.3% VS. 0%), AND MYOCARDIAL INFARCTION (0.3% VS. 0.2%). IN THE PREDEFINED CATEGORY OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) INCLUDING MI, FATAL EVENTS WERE REPORTED IN 0.6% OF OFEV-TREATED PATIENTS AND 1.8% OF PLACEBO-TREATED PATIENTS.
ADVERSE REACTIONS LEADING TO PERMANENT DOSE REDUCTIONS WERE REPORTED IN 16% OF OFEV-TREATED PATIENTS AND 1% OF PLACEBO-TREATED PATIENTS. THE MOST FREQUENT ADVERSE REACTION THAT LED TO PERMANENT DOSE REDUCTION IN THE PATIENTS TREATED WITH OFEV WAS DIARRHEA (11%).
ADVERSE REACTIONS LEADING TO DISCONTINUATION WERE REPORTED IN 21% OF OFEV-TREATED PATIENTS AND 15% OF PLACEBO-TREATED PATIENTS. THE MOST FREQUENT ADVERSE REACTIONS THAT LED TO DISCONTINUATION IN OFEV-TREATED PATIENTS WERE DIARRHEA (5%), NAUSEA (2%), AND DECREASED APPETITE (2%).
THE MOST COMMON ADVERSE REACTIONS WITH AN INCIDENCE OF GREATER THAN OR EQUAL TO 5% AND MORE FREQUENT IN THE OFEV THAN PLACEBO TREATMENT GROUP ARE LISTED IN TABLE 1.
TABLE 1: ADVERSE REACTIONS OCCURRING IN ?5% OF OFEV-TREATED PATIENTS AND MORE COMMONLY THAN PLACEBO IN STUDY 1, STUDY 2, AND STUDY 3
ADVERSE REACTION OFEV, 150 MG N=723 PLACEBO N=508
GASTROINTESTINAL DISORDERS
DIARRHEA 62% 18%
NAUSEA 24% 7%
ABDOMINAL PAINA 15% 6%
VOMITING 12% 3%
HEPATOBILIARY DISORDERS
LIVER ENZYME ELEVATIONB 14% 3%
METABOLISM AND NUTRITION DISORDERS
DECREASED APPETITE 11% 5%
NERVOUS SYSTEM DISORDERS
HEADACHE 8% 5%
INVESTIGATIONS
WEIGHT DECREASED 10% 3%
VASCULAR DISORDERS
HYPERTENSIONC 5% 4%
A INCLUDES ABDOMINAL PAIN, ABDOMINAL PAIN UPPER, ABDOMINAL PAIN LOWER, GASTROINTESTINAL PAIN AND ABDOMINAL TENDERNESS. B INCLUDES GAMMA-GLUTAMYLTRANSFERASE INCREASED, HEPATIC ENZYME INCREASED, ALANINE AMINOTRANSFERASE INCREASED, ASPARTATE AMINOTRANSFERASE INCREASED, HEPATIC FUNCTION ABNORMAL, LIVER FUNCTION TEST ABNORMAL, TRANSAMINASE INCREASED, BLOOD ALKALINE PHOSPHATASE-INCREASED, ALANINE AMINOTRANSFERASE ABNORMAL, ASPARTATE AMINOTRANSFERASE ABNORMAL, AND GAMMA-GLUTAMYLTRANSFERASE ABNORMAL. C INCLUDES HYPERTENSION, BLOOD PRESSURE INCREASED, HYPERTENSIVE CRISIS, AND HYPERTENSIVE CARDIOMYOPATHY.
IN ADDITION, HYPOTHYROIDISM WAS REPORTED IN PATIENTS TREATED WITH OFEV, MORE THAN PLACEBO (1.1% VS. 0.6%). ALOPECIA WAS ALSO REPORTED IN MORE PATIENTS TREATED WITH OFEV THAN PLACEBO (0.8% VS. 0.4%).
COMBINATION WITH PIRFENIDONE
CONCOMITANT TREATMENT WITH NINTEDANIB AND PIRFENIDONE WAS INVESTIGATED IN AN EXPLORATORY OPEN-LABEL, RANDOMIZED (1:1) TRIAL OF NINTEDANIB 150 MG TWICE DAILY WITH ADD-ON PIRFENIDONE (TITRATED TO 801 MG THREE TIMES A DAY) COMPARED TO NINTEDANIB 150 MG TWICE DAILY ALONE IN 105 RANDOMIZED PATIENTS FOR 12 WEEKS. THE PRIMARY ENDPOINT WAS THE PERCENTAGE OF PATIENTS WITH GASTROINTESTINAL ADVERSE EVENTS FROM BASELINE TO WEEK 12. GASTROINTESTINAL ADVERSE EVENTS WERE IN LINE WITH THE ESTABLISHED SAFETY PROFILE OF EACH COMPONENT AND WERE EXPERIENCED IN 37 (70%) PATIENTS TREATED WITH PIRFENIDONE ADDED TO NINTEDANIB VERSUS 27 (53%) PATIENTS TREATED WITH NINTEDANIB ALONE.
DIARRHEA, NAUSEA, VOMITING, AND ABDOMINAL PAIN (INCLUDES UPPER ABDOMINAL PAIN, ABDOMINAL DISCOMFORT, AND ABDOMINAL PAIN) WERE THE MOST FREQUENT ADVERSE EVENTS REPORTED IN 20 (38%) VERSUS 16 (31%), IN 22 (42%) VERSUS 6 (12%), IN 15 (28%) VERSUS 6 (12%), AND IN 15 (28%) VERSUS 7 (14%) PATIENTS TREATED WITH PIRFENIDONE ADDED TO NINTEDANIB VERSUS NINTEDANIB ALONE, RESPECTIVELY. MORE SUBJECTS REPORTED AST OR ALT ELEVATIONS (GREATER THAN OR EQUAL TO 3X THE UPPER LIMIT OF NORMAL) WHEN USING PIRFENIDONE IN COMBINATION WITH NINTEDANIB (N=3 (6%)) COMPARED TO NINTEDANIB ALONE (N=0) [SEE WARNINGS AND PRECAUTIONS].
CHRONIC FIBROSING INTERSTITIAL LUNG DISEASES WITH A PROGRESSIVE PHENOTYPE
OFEV WAS STUDIED IN A PHASE 3, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (STUDY 5) IN WHICH 663 PATIENTS WITH CHRONIC FIBROSING ILDS WITH A PROGRESSIVE PHENOTYPE WERE RANDOMIZED TO RECEIVE OFEV 150 MG TWICE DAILY (N=332) OR PLACEBO (N=331) FOR AT LEAST 52 WEEKS. AT 52 WEEKS, THE MEDIAN DURATION OF EXPOSURE WAS 12 MONTHS FOR PATIENTS IN BOTH TREATMENT ARMS. SUBJECTS RANGED IN AGE FROM 27 TO 87 YEARS (MEDIAN AGE OF 67 YEARS). THE MAJORITY OF PATIENTS WERE CAUCASIAN (74%) OR ASIAN (25%). MOST PATIENTS WERE MALE (54%).
THE MOST FREQUENT SERIOUS ADVERSE EVENT REPORTED IN PATIENTS TREATED WITH OFEV, MORE THAN PLACEBO, WAS PNEUMONIA (4% VS. 3%). ADVERSE EVENTS LEADING TO DEATH WERE REPORTED IN 3% OF PATIENTS TREATED WITH OFEV AND IN 5% OF PATIENTS TREATED WITH PLACEBO. NO PATTERN WAS IDENTIFIED IN THE ADVERSE EVENTS LEADING TO DEATH.
ADVERSE REACTIONS LEADING TO PERMANENT DOSE REDUCTIONS WERE REPORTED IN 33% OF OFEV-TREATED PATIENTS AND 4% OF PLACEBO-TREATED PATIENTS. THE MOST FREQUENT ADVERSE REACTION THAT LED TO PERMANENT DOSE REDUCTION IN THE PATIENTS TREATED WITH OFEV WAS DIARRHEA (16%).
ADVERSE REACTIONS LEADING TO DISCONTINUATION WERE REPORTED IN 20% OF OFEV-TREATED PATIENTS AND 10% OF PLACEBO-TREATED PATIENTS. THE MOST FREQUENT ADVERSE REACTION THAT LED TO DISCONTINUATION IN OFEV-TREATED PATIENTS WAS DIARRHEA (6%).
THE SAFETY PROFILE IN PATIENTS WITH CHRONIC FIBROSING ILDS WITH A PROGRESSIVE PHENOTYPE TREATED WITH OFEV WAS CONSISTENT WITH THAT OBSERVED IN IPF PATIENTS. IN ADDITION, THE FOLLOWING ADVERSE EVENTS WERE REPORTED IN OFEV MORE THAN PLACEBO IN CHRONIC PROGRESSIVE FIBROSING ILD: NASOPHARYNGITIS (13% VS. 12%), UPPER RESPIRATORY TRACT INFECTION (7% VS 6%), URINARY TRACT INFECTION (6% VS. 4%), FATIGUE (10% VS. 6%), AND BACK PAIN (6% VS. 5%).
SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE
OFEV WAS STUDIED IN A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (STUDY 4) IN WHICH 576 PATIENTS WITH SSC-ILD RECEIVED OFEV 150 MG TWICE DAILY (N=288) OR PLACEBO (N=288). PATIENTS WERE TO RECEIVE TREATMENT FOR AT LEAST 52 WEEKS; INDIVIDUAL PATIENTS WERE TREATED FOR UP TO 100 WEEKS. THE MEDIAN DURATION OF EXPOSURE WAS 15 MONTHS FOR PATIENTS TREATED WITH OFEV AND 16 MONTHS FOR PATIENTS TREATED WITH PLACEBO. SUBJECTS RANGED IN AGE FROM 20 TO 79 YEARS (MEDIAN AGE OF 55 YEARS). MOST PATIENTS WERE FEMALE (75%). PATIENTS WERE MOSTLY CAUCASIAN (67%), ASIAN (25%), OR BLACK (6%). AT BASELINE, 49% OF PATIENTS WERE ON STABLE THERAPY WITH MYCOPHENOLATE.
THE MOST FREQUENT SERIOUS ADVERSE EVENTS REPORTED IN PATIENTS TREATED WITH OFEV, MORE THAN PLACEBO, WERE INTERSTITIAL LUNG DISEASE (2.4% NINTEDANIB VS. 1.7% PLACEBO) AND PNEUMONIA (2.8% NINTEDANIB VS. 0.3% PLACEBO). WITHIN 52 WEEKS, 5 PATIENTS TREATED WITH OFEV (1.7%) AND 4 PATIENTS TREATED WITH PLACEBO (1.4%) DIED. THERE WAS NO PATTERN AMONG ADVERSE EVENTS LEADING TO DEATH IN EITHER TREATMENT ARM.
ADVERSE REACTIONS LEADING TO PERMANENT DOSE REDUCTIONS WERE REPORTED IN 34% OF OFEV-TREATED PATIENTS AND 4% OF PLACEBO-TREATED PATIENTS. THE MOST FREQUENT ADVERSE REACTION THAT LED TO PERMANENT DOSE REDUCTION IN THE PATIENTS TREATED WITH OFEV WAS DIARRHEA (22%).
ADVERSE REACTIONS LEADING TO DISCONTINUATION WERE REPORTED IN 16% OF OFEV-TREATED PATIENTS AND 9% OF PLACEBO-TREATED PATIENTS. THE MOST FREQUENT ADVERSE REACTIONS THAT LED TO DISCONTINUATION IN OFEV-TREATED PATIENTS WERE DIARRHEA (7%), NAUSEA (2%), VOMITING (1%), ABDOMINAL PAIN (1%), AND INTERSTITIAL LUNG DISEASE (1%).
THE SAFETY PROFILE IN PATIENTS TREATED WITH OFEV WITH OR WITHOUT MYCOPHENOLATE AT BASELINE WAS COMPARABLE.
THE MOST COMMON ADVERSE REACTIONS WITH AN INCIDENCE OF GREATER THAN OR EQUAL TO 5% IN OFEV-TREATED PATIENTS AND MORE COMMONLY THAN IN PLACEBO ARE LISTED IN TABLE 2.
TABLE 2: ADVERSE REACTIONS OCCURRING IN ?5% OF OFEV-TREATED PATIENTS AND MORE COMMONLY THAN PLACEBO IN STUDY 4
ADVERSE REACTION OFEV, 150 MG N=288 PLACEBO N=288
DIARRHEA 76% 32%
NAUSEA 32% 14%
VOMITING 25% 10%
SKIN ULCER 18% 17%
ABDOMINAL PAINA 18% 11%
LIVER ENZYME ELEVATIONB 13% 3%
WEIGHT DECREASED 12% 4%
FATIGUE 11% 7%
DECREASED APPETITE 9% 4%
HEADACHE 9% 8%
PYREXIA 6% 5%
BACK PAIN 6% 4%
DIZZINESS 6% 4%
HYPERTENSIONC 5% 2%
A INCLUDES ABDOMINAL PAIN, ABDOMINAL PAIN UPPER, ABDOMINAL PAIN LOWER, AND ESOPHAGEAL PAIN. B INCLUDES ALANINE AMINOTRANSFERASE INCREASED, GAMMA-GLUTAMYLTRANSFERASE INCREASED, ASPARTATE AMINOTRANSFERASE INCREASED, HEPATIC ENZYME INCREASED, BLOOD ALKALINE PHOSPHATASE INCREASED, TRANSAMINASE INCREASED, AND HEPATIC FUNCTION ABNORMAL. C INCLUDES HYPERTENSION, BLOOD PRESSURE INCREASED, AND HYPERTENSIVE CRISIS.
IN ADDITION, ALOPECIA WAS REPORTED IN PATIENTS TREATED WITH OFEV, MORE THAN PLACEBO (1.4% VS. 1.0%).
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POSTAPPROVAL USE OF OFEV. 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. THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POSTAPPROVAL USE OF OFEV: DRUG-INDUCED LIVER INJURY [SEE WARNINGS AND PRECAUTIONS] NON-SERIOUS AND SERIOUS BLEEDING EVENTS, SOME OF WHICH WERE FATAL [SEE WARNINGS AND PRECAUTIONS], PANCREATITIS, THROMBOCYTOPENIA, RASH, PRURITUS.
DRUG INTERACTIONS
DRUG INTERACTIONS
P-GLYCOPROTEIN (P-GP) AND CYP3A4 INHIBITORS AND INDUCERS
NINTEDANIB IS A SUBSTRATE OF P-GP AND, TO A MINOR EXTENT, CYP3A4 [SEE CLINICAL PHARMACOLOGY]. COADMINISTRATION WITH ORAL DOSES OF A P-GP AND CYP3A4 INHIBITOR, KETOCONAZOLE, INCREASED EXPOSURE TO NINTEDANIB BY 60%. CONCOMITANT USE OF P-GP AND CYP3A4 INHIBITORS (E.G., ERYTHROMYCIN) WITH OFEV MAY INCREASE EXPOSURE TO NINTEDANIB [SEE CLINICAL PHARMACOLOGY] IN SUCH CASES, PATIENTS SHOULD BE MONITORED CLOSELY FOR TOLERABILITY OF OFEV. MANAGEMENT OF ADVERSE REACTIONS MAY REQUIRE INTERRUPTION, DOSE REDUCTION, OR DISCONTINUATION OF THERAPY WITH OFEV [SEE DOSAGE AND ADMINISTRATION].
COADMINISTRATION WITH ORAL DOSES OF A P-GP AND CYP3A4 INDUCER, RIFAMPICIN, DECREASED EXPOSURE TO NINTEDANIB BY 50%. CONCOMITANT USE OF P-GP AND CYP3A4 INDUCERS (E.G., CARBAMAZEPINE, PHENYTOIN, AND ST. JOHN'S WORT) WITH OFEV SHOULD BE AVOIDED AS THESE DRUGS MAY DECREASE EXPOSURE TO NINTEDANIB [SEE CLINICAL PHARMACOLOGY].
ANTICOAGULANTS
NINTEDANIB IS A VEGFR INHIBITOR AND MAY INCREASE THE RISK OF BLEEDING. MONITOR PATIENTS ON FULL ANTICOAGULATION THERAPY CLOSELY FOR BLEEDING AND ADJUST ANTICOAGULATION TREATMENT AS NECESSARY [SEE WARNINGS AND PRECAUTIONS]
PIRFENIDONE
IN A MULTIPLE-DOSE STUDY CONDUCTED TO ASSESS THE PHARMACOKINETIC EFFECTS OF CONCOMITANT TREATMENT WITH NINTEDANIB AND PIRFENIDONE, THE COADMINISTRATION OF NINTEDANIB WITH PIRFENIDONE DID NOT ALTER THE EXPOSURE OF EITHER AGENT [SEE CLINICAL PHARMACOLOGY]. THEREFORE, NO DOSE ADJUSTMENT IS NECESSARY DURING CONCOMITANT ADMINISTRATION OF NINTEDANIB WITH PIRFENIDONE.
BOSENTAN
COADMINISTRATION OF NINTEDANIB WITH BOSENTAN DID NOT ALTER THE PHARMACOKINETICS OF NINTEDANIB [SEE CLINICAL PHARMACOLOGY].
WARNINGS & PRECAUTIONS
WARNINGS
INCLUDED AS PART OF THE PRECAUTIONS SECTION.
PRECAUTIONS
HEPATIC IMPAIRMENT
TREATMENT WITH OFEV IS NOT RECOMMENDED IN PATIENTS WITH MODERATE (CHILD PUGH B) OR SEVERE (CHILD PUGH C) HEPATIC IMPAIRMENT [SEE USE IN SPECIFIC POPULATIONS AND CLINICAL PHARMACOLOGY ]. PATIENTS WITH MILD HEPATIC IMPAIRMENT (CHILD PUGH A) CAN BE TREATED WITH A REDUCED DOSE OF OFEV [SEE DOSAGE AND ADMINISTRATION ].
ELEVATED LIVER ENZYMES AND DRUG-INDUCED LIVER INJURY
CASES OF DRUG-INDUCED LIVER INJURY (DILI) HAVE BEEN OBSERVED WITH OFEV TREATMENT. IN THE POSTMARKETING PERIOD, NON-SERIOUS AND SERIOUS CASES OF DILI, INCLUDING SEVERE LIVER INJURY WITH FATAL OUTCOME, HAVE BEEN REPORTED. THE MAJORITY OF HEPATIC EVENTS OCCUR WITHIN THE FIRST THREE MONTHS OF TREATMENT. IN CLINICAL TRIALS, ADMINISTRATION OF OFEV WAS ASSOCIATED WITH ELEVATIONS OF LIVER ENZYMES (ALT, AST, ALKP, GGT) AND BILIRUBIN. LIVER ENZYME AND BILIRUBIN INCREASES WERE REVERSIBLE WITH DOSE MODIFICATION OR INTERRUPTION IN THE MAJORITY OF CASES. THE MAJORITY (94%) OF PATIENTS WITH ALT AND/OR AST ELEVATIONS HAD ELEVATIONS LESS THAN 5 TIMES ULN. THE MAJORITY (95%) OF PATIENTS WITH BILIRUBIN ELEVATIONS HAD ELEVATIONS LESS THAN 2 TIMES ULN [SEE USE IN SPECIFIC POPULATIONS AND CLINICAL PHARMACOLOGY ]. PATIENTS WITH A LOW BODY WEIGHT (LESS THAN 65 KG), ASIAN, AND FEMALE PATIENTS MAY HAVE A HIGHER RISK OF ELEVATIONS IN LIVER ENZYMES. NINTEDANIB EXPOSURE INCREASED WITH PATIENT AGE, WHICH MAY ALSO RESULT IN A HIGHER RISK OF INCREASED LIVER ENZYMES [SEE CLINICAL PHARMACOLOGY ].
CONDUCT LIVER FUNCTION TESTS (ALT, AST, AND BILIRUBIN) PRIOR TO INITIATION OF TREATMENT WITH OFEV, AT REGULAR INTERVALS DURING THE FIRST THREE MONTHS OF TREATMENT, AND PERIODICALLY THEREAFTER OR AS CLINICALLY INDICATED. MEASURE LIVER TESTS PROMPTLY IN PATIENTS WHO REPORT SYMPTOMS THAT MAY INDICATE LIVER INJURY, INCLUDING FATIGUE, ANOREXIA, RIGHT UPPER ABDOMINAL DISCOMFORT, DARK URINE OR JAUNDICE. DOSAGE MODIFICATIONS OR INTERRUPTION MAY BE NECESSARY FOR LIVER ENZYME ELEVATIONS [SEE DOSAGE AND ADMINISTRATION ].
GASTROINTESTINAL DISORDERS
DIARRHEA
DIARRHEA WAS THE MOST FREQUENT GASTROINTESTINAL EVENT REPORTED IN 62% VERSUS 18% OF PATIENTS TREATED WITH OFEV AND PLACEBO, RESPECTIVELY [SEE ADVERSE REACTIONS ]. IN MOST PATIENTS, THE EVENT WAS OF MILD TO MODERATE INTENSITY AND OCCURRED WITHIN THE FIRST 3 MONTHS OF TREATMENT. DIARRHEA LED TO PERMANENT DOSE REDUCTION IN 11% OF PATIENTS TREATED WITH OFEV COMPARED TO 0 PLACEBO-TREATED PATIENTS. DIARRHEA LED TO DISCONTINUATION OF OFEV IN 5% OF THE PATIENTS COMPARED TO LESS THAN 1% OF PLACEBO-TREATED PATIENTS.
DOSAGE MODIFICATIONS OR TREATMENT INTERRUPTIONS MAY BE NECESSARY IN PATIENTS WITH ADVERSE REACTIONS OF DIARRHEA. TREAT DIARRHEA AT FIRST SIGNS WITH ADEQUATE HYDRATION AND ANTIDIARRHEAL MEDICATION (E.G., LOPERAMIDE), AND CONSIDER TREATMENT INTERRUPTION IF DIARRHEA CONTINUES [SEE DOSAGE AND ADMINISTRATION ]. OFEV TREATMENT MAY BE RESUMED AT THE FULL DOSAGE (150 MG TWICE DAILY), OR AT THE REDUCED DOSAGE (100 MG TWICE DAILY), WHICH SUBSEQUENTLY MAY BE INCREASED TO THE FULL DOSAGE. IF SEVERE DIARRHEA PERSISTS DESPITE SYMPTOMATIC TREATMENT, DISCONTINUE TREATMENT WITH OFEV.
NAUSEA AND VOMITING
NAUSEA WAS REPORTED IN 24% VERSUS 7% AND VOMITING WAS REPORTED IN 12% VERSUS 3% OF PATIENTS TREATED WITH OFEV AND PLACEBO, RESPECTIVELY [SEE ADVERSE REACTIONS ]. IN MOST PATIENTS, THESE EVENTS WERE OF MILD TO MODERATE INTENSITY. NAUSEA LED TO DISCONTINUATION OF OFEV IN 2% OF PATIENTS. VOMITING LED TO DISCONTINUATION OF OFEV IN 1% OF THE PATIENTS.
FOR NAUSEA OR VOMITING THAT PERSISTS DESPITE APPROPRIATE SUPPORTIVE CARE INCLUDING ANTI-EMETIC THERAPY, DOSE REDUCTION OR TREATMENT INTERRUPTION MAY BE REQUIRED [SEE DOSAGE AND ADMINISTRATION ]. OFEV TREATMENT MAY BE RESUMED AT THE FULL DOSAGE (150 MG TWICE DAILY), OR AT THE REDUCED DOSAGE (100 MG TWICE DAILY), WHICH SUBSEQUENTLY MAY BE INCREASED TO THE FULL DOSAGE. IF SEVERE NAUSEA OR VOMITING DOES NOT RESOLVE, DISCONTINUE TREATMENT WITH OFEV.
EMBRYO-FETAL TOXICITY
BASED ON FINDINGS FROM ANIMAL STUDIES AND ITS MECHANISM OF ACTION, OFEV CAN CAUSE FETAL HARM WHEN ADMINISTERED TO A PREGNANT WOMAN. NINTEDANIB CAUSED EMBRYO-FETAL DEATHS AND STRUCTURAL ABNORMALITIES IN RATS AND RABBITS WHEN ADMINISTERED DURING ORGANOGENESIS AT LESS THAN (RATS) AND APPROXIMATELY 5 TIMES (RABBITS) THE MAXIMUM RECOMMENDED HUMAN DOSE (MRHD) IN ADULTS. ADVISE PREGNANT WOMEN OF THE POTENTIAL RISK TO A FETUS. ADVISE FEMALES OF REPRODUCTIVE POTENTIAL TO AVOID BECOMING PREGNANT WHILE RECEIVING TREATMENT WITH OFEV AND TO USE EFFECTIVE CONTRACEPTION DURING TREATMENT AND AT LEAST 3 MONTHS AFTER THE LAST DOSE OF OFEV. VERIFY PREGNANCY STATUS PRIOR TO TREATMENT WITH OFEV [SEE USE IN SPECIFIC POPULATIONS AND CLINICAL PHARMACOLOGY ].
ARTERIAL THROMBOEMBOLIC EVENTS
ARTERIAL THROMBOEMBOLIC EVENTS HAVE BEEN REPORTED IN PATIENTS TAKING OFEV. IN CLINICAL TRIALS, ARTERIAL THROMBOEMBOLIC EVENTS WERE REPORTED IN 2.5% OF PATIENTS TREATED WITH OFEV AND 0.8% OF PLACEBO-TREATED PATIENTS. MYOCARDIAL INFARCTION WAS THE MOST COMMON ADVERSE REACTION UNDER ARTERIAL THROMBOEMBOLIC EVENTS, OCCURRING IN 1.5% OF OFEV-TREATED PATIENTS COMPARED TO 0.4% OF PLACEBO-TREATED PATIENTS.
USE CAUTION WHEN TREATING PATIENTS AT HIGHER CARDIOVASCULAR RISK INCLUDING KNOWN CORONARY ARTERY DISEASE. CONSIDER TREATMENT INTERRUPTION IN PATIENTS WHO DEVELOP SIGNS OR SYMPTOMS OF ACUTE MYOCARDIAL ISCHEMIA.
RISK OF BLEEDING
BASED ON THE MECHANISM OF ACTION (VEGFR INHIBITION), OFEV MAY INCREASE THE RISK OF BLEEDING. IN CLINICAL TRIALS, BLEEDING EVENTS WERE REPORTED IN 10% OF PATIENTS TREATED WITH OFEV AND IN 7% OF PATIENTS TREATED WITH PLACEBO. IN THE POSTMARKETING PERIOD NON-SERIOUS AND SERIOUS BLEEDING EVENTS, SOME OF WHICH WERE FATAL, HAVE BEEN OBSERVED.
USE OFEV IN PATIENTS WITH KNOWN RISK OF BLEEDING ONLY IF THE ANTICIPATED BENEFIT OUTWEIGHS THE POTENTIAL RISK.
GASTROINTESTINAL PERFORATION
BASED ON THE MECHANISM OF ACTION, OFEV MAY INCREASE THE RISK OF GASTROINTESTINAL PERFORATION. IN CLINICAL TRIALS, GASTROINTESTINAL PERFORATION WAS REPORTED IN 0.3% OF PATIENTS TREATED WITH OFEV, COMPARED TO 0 CASES IN THE PLACEBO-TREATED PATIENTS. IN THE POSTMARKETING PERIOD, CASES OF GASTROINTESTINAL PERFORATIONS HAVE BEEN REPORTED, SOME OF WHICH WERE FATAL. USE CAUTION WHEN TREATING PATIENTS WHO HAVE HAD RECENT ABDOMINAL SURGERY, PREVIOUS HISTORY OF DIVERTICULAR DISEASE OR RECEIVING CONCOMITANT CORTICOSTEROIDS OR NSAIDS.
DISCONTINUE THERAPY WITH OFEV IN PATIENTS WHO DEVELOP GASTROINTESTINAL PERFORATION. ONLY USE OFEV IN PATIENTS WITH KNOWN RISK OF GASTROINTESTINAL PERFORATION IF THE ANTICIPATED BENEFIT OUTWEIGHS THE POTENTIAL RISK.
PATIENT COUNSELING INFORMATION
ADVISE THE PATIENT TO READ THE FDA-APPROVED PATIENT LABELING (PATIENT INFORMATION ).
ELEVATED LIVER ENZYMES AND DRUG-INDUCED LIVER INJURY
ADVISE PATIENTS THAT THEY WILL NEED TO UNDERGO LIVER FUNCTION TESTING PERIODICALLY. ADVISE PATIENTS TO IMMEDIATELY REPORT ANY SYMPTOMS OF A LIVER PROBLEM (E.G., SKIN OR THE WHITES OF EYES TURN YELLOW, URINE TURNS DARK OR BROWN (TEA COLORED), PAIN ON THE RIGHT SIDE OF STOMACH, BLEED OR BRUISE MORE EASILY THAN NORMAL, LETHARGY, LOSS OF APPETITE) [SEE WARNINGS AND PRECAUTIONS].
GASTROINTESTINAL DISORDERS
INFORM PATIENTS THAT GASTROINTESTINAL DISORDERS SUCH AS DIARRHEA, NAUSEA, AND VOMITING WERE THE MOST COMMONLY REPORTED GASTROINTESTINAL EVENTS OCCURRING IN PATIENTS WHO RECEIVED OFEV. ADVISE PATIENTS THAT THEIR HEALTHCARE PROVIDER MAY RECOMMEND HYDRATION, ANTIDIARRHEAL MEDICATIONS (E.G., LOPERAMIDE), OR ANTI-EMETIC MEDICATIONS TO TREAT THESE SIDE EFFECTS. TEMPORARY DOSAGE REDUCTIONS OR DISCONTINUATIONS MAY BE REQUIRED. INSTRUCT PATIENTS TO CONTACT THEIR HEALTHCARE PROVIDER AT THE FIRST SIGNS OF DIARRHEA OR FOR ANY SEVERE OR PERSISTENT DIARRHEA, NAUSEA, OR VOMITING [SEE WARNINGS AND PRECAUTIONS AND ADVERSE REACTIONS ].
EMBRYO-FETAL TOXICITY
COUNSEL PATIENTS ON PREGNANCY PREVENTION AND PLANNING. ADVISE FEMALES OF REPRODUCTIVE POTENTIAL OF THE POTENTIAL RISK TO A FETUS AND TO AVOID BECOMING PREGNANT WHILE RECEIVING TREATMENT WITH OFEV. ADVISE FEMALES OF REPRODUCTIVE POTENTIAL TO USE EFFECTIVE CONTRACEPTION DURING TREATMENT, AND FOR AT LEAST 3 MONTHS AFTER TAKING THE LAST DOSE OF OFEV. ADVISE FEMALE PATIENTS TO NOTIFY THEIR DOCTOR IF THEY BECOME PREGNANT DURING THERAPY WITH OFEV [SEE WARNINGS AND PRECAUTIONS AND USE IN SPECIFIC POPULATIONS].
ARTERIAL THROMBOEMBOLIC EVENTS
ADVISE PATIENTS ABOUT THE SIGNS AND SYMPTOMS OF ACUTE MYOCARDIAL ISCHEMIA AND OTHER ARTERIAL THROMBOEMBOLIC EVENTS AND THE URGENCY TO SEEK IMMEDIATE MEDICAL CARE FOR THESE CONDITIONS [SEE WARNINGS AND PRECAUTIONS].
RISK OF BLEEDING
BLEEDING EVENTS HAVE BEEN REPORTED. ADVISE PATIENTS TO REPORT UNUSUAL BLEEDING [SEE WARNINGS AND PRECAUTIONS].
GASTROINTESTINAL PERFORATION
SERIOUS GASTROINTESTINAL PERFORATION EVENTS HAVE BEEN REPORTED. ADVISE PATIENTS TO REPORT SIGNS AND SYMPTOMS OF GASTROINTESTINAL PERFORATION [SEE WARNINGS AND PRECAUTIONS].
LACTATION
ADVISE PATIENTS THAT BREASTFEEDING IS NOT RECOMMENDED WHILE TAKING OFEV [SEE USE IN SPECIFIC POPULATIONS].
SMOKERS
ENCOURAGE PATIENTS TO STOP SMOKING PRIOR TO TREATMENT WITH OFEV AND TO AVOID SMOKING WHEN USING OFEV [SEE CLINICAL PHARMACOLOGY ].
ADMINISTRATION
INSTRUCT PATIENTS TO SWALLOW OFEV CAPSULES WHOLE WITH LIQUID AND NOT TO CHEW OR CRUSH THE CAPSULES DUE TO THE BITTER TASTE. ADVISE PATIENTS TO NOT MAKE UP FOR A MISSED DOSE [SEE DOSAGE AND ADMINISTRATION ].
NONCLINICAL TOXICOLOGY
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
TWO-YEAR ORAL CARCINOGENICITY STUDIES OF NINTEDANIB IN RATS AND MICE HAVE NOT REVEALED ANY EVIDENCE OF CARCINOGENIC POTENTIAL. NINTEDANIB WAS DOSED UP TO 10 AND 30 MG/KG/DAY IN RATS AND MICE, RESPECTIVELY. THESE DOSES WERE LESS THAN AND APPROXIMATELY 4 TIMES THE MRHD ON A PLASMA DRUG AUC BASIS.
NINTEDANIB WAS NEGATIVE FOR GENOTOXICITY IN THE IN VITRO BACTERIAL REVERSE MUTATION ASSAY, THE MOUSE LYMPHOMA CELL FORWARD MUTATION ASSAY, AND THE IN VIVO RAT MICRONUCLEUS ASSAY.
IN RATS, NINTEDANIB REDUCED FEMALE FERTILITY AT EXPOSURE LEVELS APPROXIMATELY 3 TIMES THE MRHD (ON AN AUC BASIS AT AN ORAL DOSE OF 100 MG/KG/DAY). EFFECTS INCLUDED INCREASES IN RESORPTION AND POST-IMPLANTATION LOSS, AND A DECREASE IN GESTATION INDEX. CHANGES IN THE NUMBER AND SIZE OF CORPORA LUTEA IN THE OVARIES WERE OBSERVED IN CHRONIC TOXICITY STUDIES IN RATS AND MICE. AN INCREASE IN THE NUMBER OF FEMALES WITH RESORPTIONS ONLY WAS OBSERVED AT EXPOSURES APPROXIMATELY EQUAL TO THE MRHD (ON AN AUC BASIS AT AN ORAL DOSE OF 20 MG/KG/DAY). NINTEDANIB HAD NO EFFECTS ON MALE FERTILITY IN RATS AT EXPOSURE LEVELS APPROXIMATELY 3 TIMES THE MRHD (ON AN AUC BASIS AT AN ORAL DOSE OF 100 MG/KG/DAY).
USE IN SPECIFIC POPULATIONS
PREGNANCY
RISK SUMMARY
BASED ON FINDINGS FROM ANIMAL STUDIES AND ITS MECHANISM OF ACTION [SEE CLINICAL PHARMACOLOGY ], OFEV CAN CAUSE FETAL HARM WHEN ADMINISTERED TO A PREGNANT WOMAN. THERE ARE NO DATA ON THE USE OF OFEV DURING PREGNANCY. IN ANIMAL STUDIES OF PREGNANT RATS AND RABBITS TREATED DURING ORGANOGENESIS, NINTEDANIB CAUSED EMBRYO-FETAL DEATHS AND STRUCTURAL ABNORMALITIES AT LESS THAN (RATS) AND APPROXIMATELY 5 TIMES (RABBITS) THE MAXIMUM RECOMMENDED HUMAN DOSE [SEE DATA]. ADVISE PREGNANT WOMEN OF THE POTENTIAL RISK TO A FETUS.
THE ESTIMATED BACKGROUND RISK OF MAJOR BIRTH DEFECTS AND MISCARRIAGE FOR THE INDICATED POPULATION IS UNKNOWN. IN THE U.S. GENERAL POPULATION, THE ESTIMATED BACKGROUND RISK OF MAJOR BIRTH DEFECTS IS 2% TO 4% AND MISCARRIAGE IN CLINICALLY RECOGNIZED PREGNANCIES IS 15% TO 20%.
DATA
ANIMAL DATA
IN ANIMAL REPRODUCTION TOXICITY STUDIES, NINTEDANIB CAUSED EMBRYO-FETAL DEATHS AND STRUCTURAL ABNORMALITIES IN RATS AND RABBITS AT LESS THAN AND APPROXIMATELY 5 TIMES THE MAXIMUM RECOMMENDED HUMAN DOSE (MRHD) IN ADULTS (ON A PLASMA AUC BASIS AT MATERNAL ORAL DOSES OF 2.5 AND 15 MG/KG/DAY IN RATS AND RABBITS, RESPECTIVELY). MALFORMATIONS INCLUDED ABNORMALITIES IN THE VASCULATURE, UROGENITAL, AND SKELETAL SYSTEMS. VASCULATURE ANOMALIES INCLUDED MISSING OR ADDITIONAL MAJOR BLOOD VESSELS. SKELETAL ANOMALIES INCLUDED ABNORMALITIES IN THE THORACIC, LUMBAR, AND CAUDAL VERTEBRAE (E.G., HEMIVERTEBRA, MISSING, OR ASYMMETRICALLY OSSIFIED), RIBS (BIFID OR FUSED), AND STERNEBRAE (FUSED, SPLIT, OR UNILATERALLY OSSIFIED). IN SOME FETUSES, ORGANS IN THE UROGENITAL SYSTEM WERE MISSING. IN RABBITS, A SIGNIFICANT CHANGE IN SEX RATIO WAS OBSERVED IN FETUSES (FEMALE:MALE RATIO OF APPROXIMATELY 71%:29%) AT APPROXIMATELY 15 TIMES THE MRHD IN ADULTS (ON AN AUC BASIS AT A MATERNAL ORAL DOSE OF 60 MG/KG/DAY). NINTEDANIB DECREASED POST-NATAL VIABILITY OF RAT PUPS DURING THE FIRST 4 POST-NATAL DAYS WHEN DAMS WERE EXPOSED TO LESS THAN THE MRHD (ON AN AUC BASIS AT A MATERNAL ORAL DOSE OF 10 MG/KG/DAY).
LACTATION
RISK SUMMARY
THERE IS NO INFORMATION ON THE PRESENCE OF NINTEDANIB IN HUMAN MILK, THE EFFECTS ON THE BREAST-FED INFANT OR THE EFFECTS ON MILK PRODUCTION. NINTEDANIB AND/OR ITS METABOLITES ARE PRESENT IN THE MILK OF LACTATING RATS [SEE DATA].
BECAUSE OF THE POTENTIAL FOR SERIOUS ADVERSE REACTIONS IN NURSING INFANTS FROM OFEV, ADVISE WOMEN THAT BREASTFEEDING IS NOT RECOMMENDED DURING TREATMENT WITH OFEV.
DATA
MILK AND PLASMA OF LACTATING RATS HAVE SIMILAR CONCENTRATIONS OF NINTEDANIB AND ITS METABOLITES.
FEMALES AND MALES OF REPRODUCTIVE POTENTIAL
BASED ON FINDINGS FROM ANIMAL STUDIES AND ITS MECHANISM OF ACTION, OFEV CAN CAUSE FETAL HARM WHEN ADMINISTERED TO A PREGNANT WOMAN AND MAY REDUCE FERTILITY IN FEMALES OF REPRODUCTIVE POTENTIAL [SEE USE IN SPECIFIC POPULATIONS, CLINICAL PHARMACOLOGY , AND NONCLINICAL TOXICOLOGY]. COUNSEL PATIENTS ON PREGNANCY PREVENTION AND PLANNING.
PREGNANCY TESTING
VERIFY THE PREGNANCY STATUS OF FEMALES OF REPRODUCTIVE POTENTIAL PRIOR TO TREATMENT WITH OFEV [SEE DOSAGE AND ADMINISTRATION , WARNINGS AND PRECAUTIONS, AND USE IN SPECIFIC POPULATIONS].
CONTRACEPTION
ADVISE FEMALES OF REPRODUCTIVE POTENTIAL TO AVOID BECOMING PREGNANT WHILE RECEIVING TREATMENT WITH OFEV. ADVISE FEMALES OF REPRODUCTIVE POTENTIAL TO USE EFFECTIVE CONTRACEPTION DURING TREATMENT, AND FOR AT LEAST 3 MONTHS AFTER TAKING THE LAST DOSE OF OFEV.
INFERTILITY
BASED ON ANIMAL DATA, OFEV MAY REDUCE FERTILITY IN FEMALES OF REPRODUCTIVE POTENTIAL [SEE NONCLINICAL TOXICOLOGY].
PEDIATRIC USE
SAFETY AND EFFECTIVENESS IN PEDIATRIC PATIENTS HAVE NOT BEEN ESTABLISHED.
GERIATRIC USE
OF THE TOTAL NUMBER OF SUBJECTS IN PHASE 2 AND 3 CLINICAL STUDIES OF OFEV, 60.8% WERE 65 AND OVER, WHILE 16.3% WERE 75 AND OVER. IN PHASE 3 STUDIES, NO OVERALL DIFFERENCES IN EFFECTIVENESS WERE OBSERVED BETWEEN SUBJECTS WHO WERE 65 AND OVER AND YOUNGER SUBJECTS; NO OVERALL DIFFERENCES IN SAFETY WERE OBSERVED BETWEEN SUBJECTS WHO WERE 65 AND OVER OR 75 AND OVER AND YOUNGER SUBJECTS, BUT GREATER SENSITIVITY OF SOME OLDER INDIVIDUALS CANNOT BE RULED OUT.
HEPATIC IMPAIRMENT
NINTEDANIB IS PREDOMINANTLY ELIMINATED VIA BILIARY/FECAL EXCRETION (GREATER THAN 90%). IN A PK STUDY PERFORMED IN PATIENTS WITH HEPATIC IMPAIRMENT (CHILD PUGH A, CHILD PUGH B), EXPOSURE TO NINTEDANIB WAS INCREASED [SEE CLINICAL PHARMACOLOGY ]. IN PATIENTS WITH MILD HEPATIC IMPAIRMENT (CHILD PUGH A), THE RECOMMENDED DOSAGE OF OFEV IS 100 MG TWICE DAILY [SEE DOSAGE AND ADMINISTRATION ]. MONITOR FOR ADVERSE REACTIONS AND CONSIDER TREATMENT INTERRUPTION, OR DISCONTINUATION FOR MANAGEMENT OF ADVERSE REACTIONS IN THESE PATIENTS [SEE DOSAGE AND ADMINISTRATION ]. TREATMENT OF PATIENTS WITH MODERATE (CHILD PUGH B) AND SEVERE (CHILD PUGH C) HEPATIC IMPAIRMENT WITH OFEV IS NOT RECOMMENDED [SEE WARNINGS AND PRECAUTIONS].
RENAL IMPAIRMENT
BASED ON A SINGLE-DOSE STUDY, LESS THAN 1% OF THE TOTAL DOSE OF NINTEDANIB IS EXCRETED VIA THE KIDNEY [SEE CLINICAL PHARMACOLOGY ]. ADJUSTMENT OF THE STARTING DOSE IN PATIENTS WITH MILD TO MODERATE RENAL IMPAIRMENT IS NOT REQUIRED. THE SAFETY, EFFICACY, AND PHARMACOKINETICS OF NINTEDANIB HAVE NOT BEEN STUDIED IN PATIENTS WITH SEVERE RENAL IMPAIRMENT (LESS THAN 30 ML/MIN CRCL) AND END-STAGE RENAL DISEASE.
SMOKERS
SMOKING WAS ASSOCIATED WITH DECREASED EXPOSURE TO OFEV [SEE CLINICAL PHARMACOLOGY ], WHICH MAY ALTER THE EFFICACY PROFILE OF OFEV. ENCOURAGE PATIENTS TO STOP SMOKING PRIOR TO TREATMENT WITH OFEV AND TO AVOID SMOKING WHEN USING OFEV.