尼达尼布胶囊全处方说明书
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use OFEV safely and effectively. See full prescribing information for OFEV.
OFEV? (nintedanib) capsules, for oral use
Initial U.S. Approval: 2014
----------------------------INDICATIONS AND USAGE--------------------------- OFEV is a kinase inhibitor indicated for the treatment of idiopathic pulmonary fibrosis (IPF). (1)
----------------------DOSAGE AND ADMINISTRATION----------------------- ?Recommended dosage: 150 mg twice daily approximately 12 hours apart taken with food. (2.2)
?Consider temporary dose reduction to 100 mg, treatment interruption, or discontinuation for management of adverse reactions. (2.3, 5.1, 5.2, 6)
?Prior to treatment, conduct liver function tests. (2.1, 5.1)
---------------------DOSAGE FORMS AND STRENGTHS---------------------- Capsules: 150 mg and 100 mg (3)
-------------------------------CONTRAINDICATIONS------------------------------ None
-----------------------WARNINGS AND PRECAUTIONS------------------------ ?Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with OFEV. Monitor ALT, AST, and bilirubin before and during treatment.
Temporary dosage reductions or discontinuations may be required. (2.1,
5.1)
?Gastrointestinal disorders: Diarrhea, nausea, and vomiting have occurred with OFEV. Treat patients at first signs with adequate hydration and
antidiarrheal medicine (e.g., loperamide) or anti-emetics. Discontinue
OFEV if severe diarrhea, nausea, or vomiting persists despite symptomatic treatment. (5.2)
?Embryofetal toxicity: Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. (5.3) ?Arterial thromboembolic events have been reported. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. (5.4) ?Bleeding events have been reported. Use OFEV in patients with known bleeding risk only if anticipated benefit outweighs the potential risk. (5.5)
?Gastrointestinal perforation has been reported. Use OFEV with caution when treating patients with recent abdominal surgery. Discontinue 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. (5.6)
------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (≥5%) are: diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, weight decreased, and hypertension. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY
or FDA at 1-800-FDA-1088 or https://www.wendangku.net/doc/7a8260788.html,/medwatch.
-------------------------------DRUG INTERACTIONS------------------------------
?Coadministration of P-gp and CYP3A4 inhibitors may increase nintedanib exposure. Monitor patients closely for tolerability of OFEV. (7.1)
-----------------------USE IN SPECIFIC POPULATIONS------------------------
?Nursing mothers: Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. (8.3)
?Hepatic impairment: Monitor for adverse reactions and consider dose modification or discontinuation of OFEV as needed for patients with mild
hepatic impairment. OFEV is not recommended for use in patients with
moderate or severe hepatic impairment. (8.6, 12.3)
?Renal impairment: The safety and efficacy of OFEV have not been studied in patients with severe renal impairment and end-stage renal disease. (8.7,
12.3)
?Smokers: Decreased exposure has been noted in smokers which may alter the efficacy profile of OFEV. (8.8)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved patient labeling.
Revised:
10/2014
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
1INDICATIONS AND USAGE
2DOSAGE AND ADMINISTRATION
2.1Testing Prior to OFEV Administration
2.2Recommended Dosage
2.3Dosage Modification due to Adverse Reactions
3DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
5WARNINGS AND PRECAUTIONS
5.1Elevated Liver Enzymes
5.2Gastrointestinal Disorders
5.3Embryofetal Toxicity
5.4Arterial Thromboembolic Events
5.5Risk of Bleeding
5.6Gastrointestinal Perforation
6ADVERSE REACTIONS
6.1Clinical Trials Experience
7DRUG INTERACTIONS
7.1P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers
7.2Anticoagulants
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
8.3Nursing Mothers
8.4Pediatric Use
8.5Geriatric Use
8.6Hepatic Impairment
8.7Renal Impairment
8.8Smokers
10OVERDOSAGE
11DESCRIPTION
12CLINICAL PHARMACOLOGY
12.1Mechanism of Action
12.2Pharmacodynamics
12.3Pharmacokinetics
13NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility
14CLINICAL STUDIES
16HOW SUPPLIED/STORAGE AND HANDLING
17PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
_______________________________________________________________________________________________________________________________________
FULL PRESCRIBING INFORMATION
AND
USAGE
1 INDICATIONS
OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to OFEV Administration
Conduct liver function tests prior to initiating treatment with OFEV [see Warnings and Precautions (5.1)].
2.2 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 (12.3)] 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.
2.3 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 (5.1, 5.2, 5.4, 5.6) and Adverse Reactions (6.1)].
Dose modifications or interruptions may be necessary for liver enzyme elevations. For aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times to <5 times the upper limit of normal (ULN) without signs of severe 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 (5.1) and Adverse Reactions (6.1)]. Discontinue OFEV for AST or ALT elevations >5 times ULN or >3 times ULN with signs or symptoms of severe liver damage.
3 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".
4 CONTRAINDICATIONS
None
PRECAUTIONS
AND
5 WARNINGS
5.1 Elevated Liver Enzymes
The safety and efficacy of OFEV has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Treatment with OFEV is not recommended in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT). Liver enzyme increases were reversible with dose modification or interruption and not associated with clinical signs or symptoms of liver injury. The majority (94%) of patients with ALT and/or AST elevations had elevations <5 times ULN. Administration of OFEV was also associated with elevations of bilirubin. The majority (95%) of patients with bilirubin elevations had elevations <2 times ULN [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with OFEV, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations [see Dosage and Administration (2.1, 2.3)].
5.2 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 (6.1)]. 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 <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 (2.3)]. 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 (6.1)]. 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 (2.3)]. 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.
5.3 Embryofetal Toxicity
OFEV can cause fetal harm when administered to a pregnant woman. Nintedanib was teratogenic and embryofetocidal in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on an AUC basis at oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). If OFEV is used during pregnancy, or if the patient becomes pregnant while taking OFEV, the patient should be advised of the potential hazard to a fetus. Women of childbearing potential should be advised
to avoid becoming pregnant while receiving treatment with OFEV and to use adequate contraception during treatment and at least 3 months after the last dose of OFEV [see Use in Specific Populations (8.1)].
5.4 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.
5.5 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.
Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
5.6 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.
Use caution when treating patients who have had recent abdominal surgery. 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.
REACTIONS
6 ADVERSE
The following adverse reactions are discussed in greater detail in other sections of the labeling:
?Liver Enzyme and Bilirubin Elevations [see Warnings and Precautions (5.1)]
?Gastrointestinal Disorders [see Warnings and Precautions (5.2)]
?Embryofetal Toxicity [see Warnings and Precautions (5.3)]
?Arterial Thromboembolic Events [see Warnings and Precautions (5.4)]
?Risk of Bleeding [see Warnings and Precautions (5.5)]
?Gastrointestinal Perforation [see Warnings and Precautions (5.6)]
6.1 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 with over 200 patients exposed to OFEV for more than 2 years in clinical trials.
OFEV was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Studies 2 and 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 ≥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 Studies 1, 2, and 3
Adverse Reaction OFEV, 150 mg
n=723 Placebo n=508
Gastrointestinal disorders
Diarrhea 62% 18%
Nausea 24% 7%
Abdominal pain a 15% 6%
Vomiting 12% 3%
Hepatobiliary disorders
Liver enzyme elevation b 14% 3% Metabolism and nutrition disorders
Decreased appetite 11% 5%
Nervous systemic disorders
Headache 8% 5%
Investigations
Weight decreased 10% 3%
Vascular disorders
Hypertension c 5% 4%
a Includes abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain and abdominal tenderness.
b Includes gamma-glutamyltransferase increased, hepati
c 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, bloo
d pressur
e increased, hypertensive crisis, and hypertensive cardiomyopathy.
In addition, hypothyroidism was reported in patients treated with OFEV, more than placebo (1.1% vs. 0.6%).
7 DRUG
INTERACTIONS
7.1 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 (12.3)]. 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 (12.3)]. 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 (2.3)].
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 (12.3)].
7.2 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 (5.5)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D. [See Warnings and Precautions (5.3)]
OFEV can cause fetal harm when administered to a pregnant woman. If OFEV is used during pregnancy, or if the patient becomes pregnant while taking OFEV, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with OFEV.
In animal reproduction toxicity studies, nintedanib caused embryofetal deaths and teratogenic effects 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).
8.3 Nursing Mothers
Nintedanib and/or its metabolites are excreted into the milk of lactating rats. Milk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites. Excretion of nintedanib and/or its metabolites into human milk is probable. There are no human studies that have investigated the effects of OFEV on breast-fed infants. Because of the potential for serious adverse reactions in nursing infants from OFEV, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 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.
8.6 Hepatic Impairment
Nintedanib is predominantly eliminated via biliary/fecal excretion (>90%) [see Clinical Pharmacology (12.3)]. No dedicated pharmacokinetic (PK) study was performed in patients with hepatic impairment. Monitor for adverse reactions and consider dose modification or discontinuation of OFEV as needed for patients with mild hepatic impairment (Child Pugh A). The safety and efficacy of nintedanib has not been investigated in patients with hepatic impairment classified as Child Pugh B or C. Therefore, treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended [see Warnings and Precautions (5.1)].
8.7 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 (12.3)]. 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 (<30 mL/min CrCl) and end-stage renal disease.
8.8 Smokers
Smoking was associated with decreased exposure to OFEV [see Clinical Pharmacology (12.3)], 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.
10 OVERDOSAGE
In the trials, one patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A non-serious adverse event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events. Overdose was also reported in two patients in oncology studies who were exposed to a maximum of 600 mg twice daily for up to 8 days. Adverse events reported were consistent with the existing safety profile of OFEV. Both patients recovered. In case of overdose, interrupt treatment and initiate general supportive measures as appropriate.
11 DESCRIPTION
OFEV capsules contain nintedanib, a kinase inhibitor [see Mechanism of Action (12.1)]. 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).
Its structural formula is:
N N N H N H
O N C H 3O
O
O C
H 3CH 3
C H 3S
O O
Nintedanib esylate is a bright yellow powder with an empirical formula of C 31H 33N 5O 4·C 2H 6O 3S and a molecular weight of 649.76 g/mol.
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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Nintedanib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fms-like tyrosine kinase-3 (FLT3). Among them, FGFR, PDGFR, and VEGFR have been implicated in IPF pathogenesis. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signaling which is crucial for the proliferation, migration, and
transformation of fibroblasts representing essential mechanisms of the IPF pathology. In addition, nintedanib inhibits the following nRTKs: Lck, Lyn and Src kinases. The contribution of FLT3 and nRTK inhibition to IPF efficacy is unknown.
12.2 Pharmacodynamics
Cardiac Electrophysiology
In a study in renal cell cancer patients, QT/QTc measurements were recorded and showed that a single oral dose of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days did not prolong the QTcF interval.
12.3 Pharmacokinetics
The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, and cancer patients. The PK of nintedanib is linear. Dose proportionality was shown by an increase of nintedanib exposure with increasing doses (dose range 50 to 450 mg once daily and 150 to 300 mg twice daily). Accumulation upon multiple administrations in patients with IPF was 1.76-fold for AUC. Steady-state plasma concentrations were achieved within one week of dosing. Nintedanib trough concentrations remained stable for more than one year. The inter-individual variability in the PK of nintedanib was moderate to high (coefficient of variation of
standard PK parameters in the range of 30% to 70%), intra-individual variability low to moderate (coefficients of variation below 40%).
Absorption
Nintedanib reached maximum plasma concentrations approximately 2 to 4 hours after oral administration as a soft gelatin capsule under fed conditions. The absolute bioavailability of a 100 mg dose was 4.7% (90% CI: 3.62 to 6.08) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.
After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (90% CI: 95.3% to 152.5%) and absorption was delayed (median t max fasted: 2.00 hours; fed: 3.98 hours), irrespective of the food type.
Distribution
Nintedanib follows bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution which was larger than total body volume (V ss: 1050 L) was observed.
The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.87.
Elimination
The effective half-life of nintedanib in patients with IPF was 9.5 hours (gCV 31.9%). Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min; gCV 28.8%). Urinary excretion of unchanged drug within 48 hours was about 0.05% of the dose after oral and about 1.4% of the dose after intravenous administration; the renal clearance was 20 mL/min.
Metabolism
The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP 3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism, and elimination study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.
Excretion
The major route of elimination of drug-related radioactivity after oral administration of [14C] nintedanib was via fecal/biliary excretion (93.4% of dose), and the majority of OFEV was excreted as BIBF 1202. The contribution of renal excretion to the total clearance was low (0.65% of dose). The overall recovery was considered complete (above 90%) within 4 days after dosing.
Specific Populations
Age, Body Weight, and Sex
Based on population PK analysis, age and body weight were correlated with nintedanib exposure. However,
t heir effects on exposure are not sufficient to warrant a dose adjustment. There was no influence of sex on the exposure of nintedanib.
Renal Impairment
Based on a population PK analysis of data from 933 patients with IPF, exposure to nintedanib was not influenced by mild (CrCl: 60 to 90 mL/min; n=399) or moderate (CrCl: 30 to 60 mL/min; n=116) renal impairment. Data in severe renal impairment (CrCl below 30 mL/min) was limited.
Hepatic Impairment
No dedicated PK study was conducted in patients with hepatic impairment. As nintedanib is eliminated primarily by biliary/fecal excretion (>90%), hepatic impairment is likely to increase plasma nintedanib concentrations. Clinical studies excluded patients with AST or ALT greater than 1.5 times ULN. Patients with total bilirubin greater than 1.5 times ULN were also excluded. Therefore, monitor for adverse reactions and consider dose modification or discontinuation of OFEV as needed for patients with mild hepatic impairment. Smokers
In the population PK analysis, the exposure of nintedanib was 21% lower in current smokers compared to
ex- and never-smokers. The effect is not sufficient to warrant a dose adjustment.
Drug Interaction Studies
Potential for Nintedanib to Affect Other Drugs
Effect of nintedanib coadministration on pirfenidone AUC and C max was evaluated in a multiple-dose study. Nintedanib did not have an effect on the exposure of pirfenidone.
In in vitro studies, nintedanib was shown not to be an inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2. In vitro studies also showed that nintedanib has weak inhibitory potential on OCT-1, BCRP, and
P-gp; these findings are considered to be of low clinical relevance. Nintedanib and its metabolites, BIBF 1202 and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in vitro.
Potential for Other Drugs to Affect Nintedanib
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with the P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on C max in a dedicated drug-drug interaction study. In a drug-drug interaction study with the P-gp and CYP3A4 inducer, rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on C max upon coadministration with rifampicin compared to administration of nintedanib alone.
Based on a multiple-dose study in Japanese IPF patients, exposure to nintedanib decreased to 68.3% based on AUC and to 59.2% based on C max upon coadministration with pirfenidone compared to administration of nintedanib alone.
Nintedanib displays a pH-dependent solubility profile with increased solubility at acidic pH<3. However, in the clinical trials, coadministration with proton pump inhibitors or histamine H2 antagonists did not influence the exposure (trough concentrations) of nintedanib.
In in vitro studies, nintedanib was shown not to be a substrate of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, MRP-2, or BCRP. In vitro studies also showed that nintedanib was a substrate of OCT-1; these findings are considered to be of low clinical relevance.
TOXICOLOGY
13 NONCLINICAL
13.1 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).
STUDIES
14 CLINICAL
The clinical efficacy of OFEV has been studied in 1231 patients with IPF in one phase 2 (Study 1) and two phase 3 (Studies 2 and 3). These were randomized, double-blind, placebo-controlled studies comparing treatment with OFEV 150 mg twice daily to placebo for 52 weeks.
Studies 2 and 3 were identical in design. Study 1 was very similar in design. Patients were randomized in a 3:2 ratio (1:1 for Study 1) to either OFEV 150 mg or placebo twice daily for 52 weeks. Study 1 also included other treatment arms (50 mg daily, 50 mg twice daily, and 100 mg twice daily) that are not further discussed. The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC). Time to first acute IPF exacerbation was a key secondary endpoint in Studies 2 and 3 and a secondary endpoint in Study 1. Change from baseline in FVC percent predicted and survival were additional secondary endpoints in all studies.
Patients were required to have a diagnosis of IPF (ATS/ERS/JRS/ALAT criteria) for <5 years. Diagnoses were centrally adjudicated based on radiologic and, if applicable, histopathologic confirmation. Patients were required to be ≥40 years of age with an FVC ≥50% of predicted and a carbon monoxide diffusing capacity (DLCO, corrected for hemoglobin) 30% to 79% of predicted. Patients with relevant airways obstruction (i.e., pre-bronchodilator FEV1/FVC <0.7) or, in the opinion of the investigator, likely to receive a lung transplant during the studies were excluded (being listed for lung transplant was acceptable for inclusion). Patients with >1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded from the studies. Patients were also excluded if they received other investigational therapy, azathioprine, cyclophosphamide, or cyclosporine A within 8 weeks of entry into this trial, or n-acetyl cysteine and prednisone (>15 mg/day or equivalent) within 2 weeks. The majority of patients were Caucasian (60%) or Asian (30%) and male (79%). Patients had a mean age of 67 years and a mean FVC percent predicted of 80%.
Annual Rate of Decline in FVC
A statistically significant reduction in the annual rate of decline of FVC (in mL) was demonstrated in patients receiving OFEV compared to patients receiving placebo based on the random coefficient regression model, adjusted for gender, height, and age. The treatment effect on FVC was consistent in all 3 studies. See Table 2 for individual study results.
Tabl
Numb Rate a Comp D 9a
Rand b Estim
Figu obse Wee
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bid =
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le 2 Annu ber of analyzed of decline ove parison vs plac Difference b 95% CI domized set in mated based on ure 1 display erved FVC ch ek 52. Simila ure 1 Mean twice daily nge from Ba ure 2 present dicted at Wee ining was lo ual Rate of D d patients er 52 weeks cebo Study 1; treate n a random coe s the change hange from ar plots were n (SEM) Ob aseline in Per s the cumula ek 52 for Stu wer on OFE Decline in F Study 1 OFEV 150 mg twice daily 84 -60 1(27ed set in Studie efficient regres e from baseli baseline wa e seen for Stu bserved FV rcent Predict ative distribu udy 2. For al EV than on p FVC (mL) in y Placebo 83 -191 131 , 235) es 2 and 3 sion model
ine over time s plotted ove udies 1 and 3VC Change f ted Forced V ution for all ll categorical placebo. Stud n Studies 1,Study 2 OFEV 150 mg twice dai 309 -115 (7e in both tre er time, the c 3.
from Baseli Vital Capacit cut-offs for l declines in dy 3 showed , 2, and 3a
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bo OFE 150 twice 320 -1ups for Study rged at all tim ver Time in
from baselin on, the propo ults.
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ne in FVC pe ortion of pat acebo
219 207 he mean rough ercent tients
Figure 2 Cumulative Distribution of Patients by Change in Percent Predicted FVC from Baseline to Week 52 (Study 2).* The vertical lines indicate ≥0% decline or ≥10% decline.
*Missing data for change from baseline at Week 52 in percent predicted FVC (due to death, lost to follow-up or censoring before
52 weeks) was imputed using the worst decline from baseline at Week 52 observed among all patients with available data, regardless of treatment.
bid = twice daily
Time to First Acute IPF Exacerbation
Acute IPF exacerbation was defined as unexplained worsening or development of dyspnea within 30 days, new diffuse pulmonary infiltrates on chest x-ray, and/or new high-resolution CT parenchymal abnormalities with no pneumothorax or pleural effusion, and exclusion of alternative causes. Acute IPF exacerbation was adjudicated in Studies 2 and 3. In Studies 1 (investigator-reported) and 3 (adjudicated), the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving OFEV compared to placebo (hazard ratio [HR]: 0.16, 95% CI: 0.04, 0.71) and (HR:0.20, 95% CI: 0.07, 0.56), respectively. In Study 2 (adjudicated), there was no difference between the treatment groups (HR: 0.55, 95% CI: 0.20, 1.54).
Survival
Survival was evaluated for OFEV compared to placebo in Studies 2 and 3 as an exploratory analysis to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, irrespective of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference (See Figure 3).
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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 (5.2) and Adverse Reactions (6.1)].
Pregnancy
Counsel patients on pregnancy planning and prevention. Advise females of childbearing potential of the potential hazard to a fetus and to avoid becoming pregnant while receiving treatment with OFEV. Advise females of childbearing potential to use adequate 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 (5.3) and Use in Specific Populations (8.1)].
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 (5.4)].
Risk of Bleeding
Bleeding events have been reported. Advise patients to report unusual bleeding [see Warnings and Precautions (5.5)].
Gastrointestinal Perforation
Serious gastrointestinal perforation events have been reported. Advise patients to report signs and symptoms of gastrointestinal perforation [see Warnings and Precautions (5.6)].
Nursing Mothers
Advise patients to discontinue nursing while taking OFEV or discontinue OFEV while nursing [see Use in Specific Populations (8.3)].
Smokers
Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using with OFEV [see Clinical Pharmacology (12.3)].
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 (2)]. Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Licensed from:
Boehringer Ingelheim International GmbH
OFEV is a registered trademark of and used under license from Boehringer Ingelheim International GmbH.
Copyright ? 2014 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED
IT5950BJ142014
10009642/02
Patient Information
OFEV?(OH-fev)
(nintedanib)
capsules
Read this Patient Information before you start taking OFEV and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.
What is the most important information I should know about OFEV?
OFEV can cause birth defects or death to an unborn baby. Women should not become pregnant while taking OFEV. Women who are able to become pregnant should use birth control during treatment and for at least 3 months after treatment. If you become pregnant while taking OFEV, tell your doctor right away. What is OFEV?
?OFEV is a prescription medicine used to treat people with a lung disease called idiopathic pulmonary fibrosis (IPF).
?It is not known if OFEV is safe and effective in children.
What should I tell my doctor before taking OFEV?
Before you take OFEV, tell your doctor if you:
?have liver problems
?have heart problems
?have a history of blood clots
?have a bleeding problem or a family history of a bleeding problem
?have had recent surgery in your stomach (abdominal) area
?are a smoker
?have any other medical conditions
?are pregnant or plan to become pregnant. OFEV can harm your unborn baby. OFEV can cause birth defects or death to an unborn baby. See “What is the most important information I should know about OFEV?”
?are breastfeeding or plan to breastfeed. It is not known if OFEV passes into your breast milk. You and your doctor should decide if you will take OFEV or breastfeed. You should not do both.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements such as St. John’s wort. Keep a list of the medicines you take and show it to your doctor and pharmacist when you get a new medicine.
How should I take OFEV?
?Take OFEV exactly as your doctor tells you to take it.
?Your doctor will tell you how much OFEV to take and when to take it.
?Take OFEV with food. Swallow the OFEV capsules whole with a liquid.
?Do not chew or crush OFEV capsules.
?If you miss a dose of OFEV, take your next dose at your regular time. Do not take the missed dose.
?Do not take more than 300 mg of OFEV in 1 day.
?If you take too much OFEV, call your doctor or go to the nearest hospital emergency room right away. ?Your doctor should do certain blood tests before you start taking OFEV.
What are the possible side effects of OFEV?
OFEV may cause serious side effects, including:
?See “What is the most important information I should know about OFEV?”
?liver problems. Call your doctor right away if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea colored) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, or feeling tired.
Your doctor will do blood tests regularly to check how well your liver function is working during your treatment with OFEV.
?diarrhea, nausea, and vomiting. While you are taking OFEV, your doctor may recommend that you drink fluids or take medicine to treat these side effects. Tell your doctor if you have diarrhea, nausea, or
vomiting or if these symptoms do not go away or become worse. Tell your doctor if you are taking over-the-counter laxatives, stool softeners, and other medicines or dietary supplements that can cause diarrhea.
?heart attack. Tell your doctor right away if you have symptoms of a heart problem. These symptoms may include chest pain or pressure, pain in your arms, back, neck or jaw, or shortness of breath.
?stroke. Tell your doctor right away if you have symptoms of a stroke. These symptoms may include numbness or weakness on 1 side of your body, trouble talking, headache, or dizziness.
?bleeding problems. OFEV may increase your chances of having bleeding problems. Tell your doctor if you have unusual bleeding, bruising, or wounds that do not heal. Tell your doctor if you are taking a blood thinner, including prescription blood thinners and over-the-counter aspirin.
?tear in your stomach or intestinal wall (perforation). OFEV may increase your chances of having a tear in your stomach or intestinal wall. Tell your doctor if you have pain or swelling in your stomach area.
The most common side effects of OFEV are diarrhea, nausea, stomach pain, vomiting, liver problems, decreased appetite, headache, and weight loss.
These are not all the possible side effects of OFEV. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store OFEV?
?Store OFEV at room temperature between 68°F to 77°F (20°C to 25°C).
?Keep OFEV dry and protect from high heat.
?Safely throw away any OFEV that is out of date or no longer needed.
Keep OFEV and all medicines out of reach of children.
General information about the safe and effective use of OFEV.
? Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use OFEV for any condition for which it was not prescribed. Do not give OFEV to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about OFEV. If you would like more information, talk to your doctor. You can ask your pharmacist or doctor for information about OFEV that is written for health professionals.
?For more information, go to https://www.wendangku.net/doc/7a8260788.html, or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or (TTY) 1-800-459-9906, or scan the code below to go to https://www.wendangku.net/doc/7a8260788.html,.
What are the ingredients in OFEV?
Active ingredient: nintedanib.
Inactive ingredients: Fill Material: triglycerides, hard fat, lecithin. Capsule Shell: gelatin, glycerol, titanium dioxide, red ferric oxide, yellow ferric oxide, black ink.
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA
OFEV is a registered trademark of and used under license from Boehringer Ingelheim International GmbH. Copyright ? 2014 Boehringer Ingelheim International GmbH, ALL RIGHTS RESERVED
Issued: October 2014
IT5950BJ142014, 10009642/02
This Patient Information has been approved by the U.S. Food and Drug Administration.
管理系统操作说明
目录 目录 (1) 前言 .............................................................................................................................. - 3 -第一部分：前期准备.................................................................................................. - 4 - 1、注册及登录 (4) 2、修改会员资料 (5) 3、设置子账户 (6) 4、内部发文 (8) 5、留言反馈 (9) 6、设置学校信息 (10) 第二部分：人事安排................................................................................................ - 12 - 1、教师管理 (12) 2、职工管理 (13) 第三部分：课程安排................................................................................................ - 15 - 1、课程设置 (15) 2、套餐设置 (17) 3、课程计划管理 (20) 4、查看课程 (22) 第四部分：招生咨询................................................................................................ - 22 - 1、学生管理 (22) 2、咨询管理 (25) 2.1、课程咨询管理 ............................................................................................ - 25 - 2.2、套餐咨询管理 ............................................................................................ - 28 - 3、试听管理 (30) 3.1、课程试听管理 ............................................................................................ - 30 -
超药品说明书用药管理制度
《超药品说明书用药管理制度》 第一条为规范临床超药品说明书用药的管理和使用，保证临床用药安全、有效、经济，防范医疗事故和医疗纠纷，依据《中华人民共和国药品管理法》、《中华人民共和国药品管理法实施条例》、《医疗机构药事管理规定》、《处方管理办法》、《药品说明书和标签管理规定》、《中华人民共和国侵权责任法》、《新型抗肿瘤药物临床应用指导原则（2019年版）》、《超说明书用药专家共识》（中国药理学会治疗药物监测研究专业委员会药品风险管理学组）等，特制定本院《超药品说明书用药管理制度》。 第二条超药品说明书用药是指药品使用的人群、适应证、给药途径、剂量、疗程等未在药品监督管理部门批准的药品说明书记载范围内的用法，也有称为“超范围用药”、“药品说明书外用法”、“药品未注册用法”。 《医疗机构药事管理规定》和《处方管理办法》等相关医疗法规均规定须按照药品说明书合理使用药物，超药品说明书用药不受法律保护，超说明书用药导致不良后果的，医生将可能承担相应法律责任。处方医师在考虑药品的超说明书使用前，应熟悉相关法律法规，保留相关证据，最大限度防范医疗风险。 第三条超说明书用药原则 (1) 超说明书用药目的 只有在患者确因病情需要，而无其他合理的可替代药物治疗方案时，方可采用药品说明书中未明确规定、但具有明确的循证医学证据的药品用法，而不是以试验研究或其他关乎医师自身利益为目的的使用。 如果市场存在可替代药品，应当优先选择该药品，而不应当超说明书用药。 (2)权衡利弊，保障患者利益最大化 超说明书用药时，应当在无同等获益的临床试验的情况下，并充分考虑药品不良反应、禁忌证、注意事项等，权衡患者获得的利益和可能带来的风险，以保障患者利益最大化。 (3)有合理的循证医学证据支持，采纳依据满足下列条件之一（均为最新版）： ①国内、外相同通用名称药品的说明书中已注明的适应证或用法, 如美国FDA、欧盟EMA、日本MHLW等；； ②国内、外医学或药学权威协会、学术机构发布的诊疗规范、指南认可的超说明书用药，如CSCO（中国临床肿瘤学会）指南、NCCN（美国国立综合癌症网
课程设计设计说明书格式规范
课程设计设计说明书格式规范
课程设计设计说明书格式规范 一、课程设计设计说明书格式规范 装订成册的书面说明书和完整电子文档各一份，说明书统一采用A4纸打印，说明书格式如下，顺序为： （一）封面 （二）索命数正文，包括： 1、摘要（包括中文摘要和英文摘要）： 分别为300字左右，应包括：工作目的、内容、结论、关键词 2、目录 以上部分以I、II……编制页码。以下部分根据章节编写序号和页码。 3、主体部分（不少于1 字,按要求设定页眉页角，要求居中） 主要包括引言或绪论、正文、结论、致谢，采用全角符号，英文和数字半角。每页28行、每行32-35个汉字，1.5倍行间距 3.1格式：主体部分的编写格式由引言(绪论)开始，以结论结束。主体部分必须由1页开始。一级标题之间换页，二级标题之间空行。 3.2序号 3.2.1毕业说明书各章应有序号，序号用阿拉伯数字编码，层
次格式为：1××××（三号黑体，居中）×××××××××××××××××××××× (内容用小四号宋体)。 1.1××××（小三号黑体，居左） ××××××××××××××××××××× （内容用小四号宋体）。 1.1.1××××（四号黑体，居左） ×××××××××××××××××××× （内容用小四号宋体）。 ①××××（用与内容同样大小的宋体） 1）××××（用与内容同样大小的宋体）a．××××（用与内容同样大小的宋体） 3.2.2说明书中的图、表、公式、算式等，一律用阿拉伯数字分别依序连编号编排序号。序号分章依序编码，其标注形式应便于互相区别，可分别为：图 2.1、表 3.2式（3.5）等 3.2.3说明书一律用阿拉伯数字连续编页码。页码由前言（或绪论）的首页开始，作为第1页，并为右页另页。题名页、摘要、目次页等前置部分可单独编排页码。页码必须统一标注每页页脚中部。力求不出空白页，如有，仍应以右页作为单页页码。 3.2.4说明书的附录依序用大写正体英文字母A、B、C……编序号，如：附录A。
学生信息管理系统详细设计说明书
学生信息管理系统详细设计 1引言 1.1编写目的 为了彻底解决了长期困扰教学信息化工作当中安全性、可靠性的问题；为了使管理人员可以随时看到更新的数据，极大地提高信息传递的速度；为了管理者再也不必为聘用专门的操作人员来给众多教师编辑学生成绩资料而殚精竭虑，在此，设计了学生课程成绩查询管理信息系统，使得各个使用者在操作上，从此变得那么从容简单，省时又省心。 1.2系统模块的实现 在系统中包括以下功能：系统管理、学籍信息管理、课程信息管 理、成绩信息管理、帮助。分为以下几个模块 主窗体 1.3登录模块 为了系统的安全，在进入系统之前首先会出现一个登录模块，用户只有在输入正确的用户名和正确的密码之后，才能进入系统。
用户登录窗体中放置了两个文本框（Textbox）,用来输入用户名和密码；两个按钮（CommandButton）用来确定或者取消登录。 设置一个SSTab控件，供不同用户登录时选择用户权限，超级用户拥有一切权限（包括添加删除和修改以及对用户的管理），普通用户拥有受限制的权限（查询及修改密码），提高了数据库的安全性。 1.4系统管理模块 1.4.1添加用户窗体的创建 进入系统后，将会出现一个主窗体，选择系统管理模块下的添加用户，就可以进入添加用户窗体，可以通过该窗体增加新的用户。 在这个窗体中放置了三个文本框，用来输入用户名和密码；两个按钮用来确定是否添加用户；三个标签用来标示文本框的提示。 1.4.2修改密码窗体的创建 在系统管理模块下，进入修改密码窗体，用户可根据需要修改自己的密码。 在这个窗体中放置了两个文本框，用来输入密码和确认密码；两个按钮用来确定是否修改密码；两个标签用来标示文本框的内容。 1.5学籍管理模块 1.5.1添加学籍信息功能 选择主窗体中学籍管理模块下的添加学籍信息，就可进入添加学籍信息的窗体，在该窗体中我们可以对学生的学号、姓名、性别、出生日期、班号等学生的信息进行添加。设计时我尽可能设想各种边界条件，如记录为空，输入为空，输入出错等，当输入的信息满足这些边界条件时，将会弹出一个提示框提醒用户，以便用户能及时地做出修改。添加的信息将全部存储到数据库中。 在窗体上放置多个文本框和下拉式文本框，用来输入学籍信息；两个按钮用来确定是否输入学籍信息；一个按钮用来退出窗体；多个标签用来提示文本框中需要输入的内容。 1.5.2修改学籍信息功能 点击学籍管理模块下的修改学籍信息，就进入修改学籍信息的窗体，在该窗体中我们可以对前面添加的学籍信息进行修改。由于用户的需求不同，有的是要对学生的信息做个
药品超说明书用药管理规定
超说明书用药管理规定 1、超药品说明书用药(Off-label uses)的定义是指临床实际使用 药品的适应证、给药方法或剂量不在具有法律效力的说明书之内的用法，包括年龄、给药剂量、适应人群、适应证、用药方法或给药途径等与药品说明书中的用法不同的情况，又称超范围用药、药品未注册用药或药品说明书之外的用法。 2、指导思想：依据《药品管理办法》、《医疗机构药事管理规定》、 《侵权责任法》、《药品说明书和标签管理规定》，为加强药事管理工作，保证医院药学服务安全；促进临床合理用药，保障临床用药的安全性、有效性、合理性及药师自身安全，避免不必要的纠纷。 3、重要性：超药品说明书用药现象的存在具有一定的合理性和 必要性，但是超说明书用药有可能没有大量临床研究数据支持，也没有获得药品监管部门批准，因此就必然存在一定的风险，且药品说明书具有法律效力，超药品说明书用药不受法律保护，超说明书用药导致不良后果的，医生和药师要承担相应法律责任。 4、《处方管理办法》第五章规定：药师应按照药品说明书或者处 方用法，进行用药交代与指导。药师应当对处方用药适宜性进行审核，审核内容包括处方用药与临床诊断的相符性、剂量用法的正确性、其他用药不适宜情况等。药师经处方审核后，认为存在用药不适宜时，应当告之处方医师，请其确认或者重新开具处方，药师发现严重不合理用药或者用药错误，应当拒绝调剂。
5、药师在审核处方或医嘱时，首先应对药品说明书有深入、细 致、透彻地了解，并以药品说明书为依据，严格按药品说明书规范调剂药品，规避用药风险，确保调剂行为的安全及患者的用药安全。 6、当临床医生因医疗创新确需要超药品说明书用药时，应提供权 威的文献依据，并经药事委员会审核同意，报医务科备案，使用时与患者签署知情同意书。药师在审核和调剂超药品说明书用药处方或医嘱时，严格依据《知情同意书》和医务科备案方能调剂药品。 7、药师应该有自我保护意识，超说明书用药存在严重违反“用法、 用量和注意事项”之规定，即便是已签署《超说明书用药知情同意书》和医务科备案外，药师也应当依法拒绝调配，或通过《药师与医师联系表》进行合理用药干预，详细指明处方中存在的问题，请开方医师重新开具合理处方，认真把好合理用药关。 8、临床药师对超说明书用药情况认真分析其合理性、并进行调研 核准，对住院超说明书用药患者开展药物监测工作，对超说明书用药疗效进行认真分析、评价，对超说明书用药导致的药物不良反应及时分析原因，并上报医务科和通知相关病区，减少和防止因超说明书用药导致不良反应的重复发生。
产品设计说明书 模板
百度文库 项目编号： 工程编号： 版本号： 保密级别：打磨焊缝及周围热影响区 球罐焊缝（表面是 末）吸附罐 壁 移动小 车 摄像 照明设 备 固定小 车 接触罐 壁 打磨焊 缝 打磨热 影响区 能量转 换 xyz向 移动打 磨头 机密绝密产品设计说明书 产品名称： 产品型号： 工程编号： 设计： 编写： 校核： 审核： 0001年1月1日
XXX产品设计说明书 目录 NO TABLE OF CONTENTS ENTRIES FOUND.
XXX产品设计说明书 1．背景及意义 根据我国有关规程规定，根据基础情况，每隔2-6年需对大型球罐或圆柱形储罐检测一次，每隔2年需对使用5年以上的管线进行检测（通常，在低洼、潮湿的地方挖开数处检查）。各项检测之前，都必须进行罐体的清洗打磨。目前国内传统的清洗和打磨方法主要利用人工手持打磨设备进行打磨，存在着劳动强度大，施工周期长、安全性差等问题。 随着我国大型石油储罐的大量建设，以及人类对环境保护问题的日益重视，人工作业已不符合环境和发展的客观要求，淘汰人工作业是历史的必然。机器人技术的出现和发展，以及检测人员自我保护意识的增强，使得机器人代替人工进行罐壁打磨作业成为迫切任务。本项目开发的能携带自动化打磨装备的爬壁机器人，可以大大降低大型容器打磨作业的成本，提高工作效率，特别是把检测人员从危险作业环境中解脱出来。因此，大型容器壁面打磨机器人的研制具有重要的社会效益、经济意义和广阔的应用前景。 2．设计需求分析 需求表汇总 表XXX产品设计需求表 基本需求 名称内容小车最大尺寸 焊缝打磨宽度 越障高度 自重和承载 能量要求 功能需求 名称内容 吸附功能 机器人在罐壁工作时，应可靠地吸附在球罐内、外表面，且吸附力 不能过大。 移动转向功能
超说明书用药管理制度
医院药品超说明书用药管理制度 (征求意见稿) 为进一步加强我院药事管理，保障病人用药安全，降低医疗风险，根据《中华人民共和国药品管理法》、《医疗机构药事管理规定》、《处方管理办法》、《药品说明书和标签管理规定》等法律法规，结合我院实际情况，特制定本管理规定。 一、超说明书用药的定义 超说明书用药是指临床实际使用药品的适应证、给药方法或者剂量不在具有法律效力的说明书之内的用法，包括年龄、给药剂量、适应人群、适应证、用药方法或给药途径等与药品说明书中的用法不同的情况，又称超范围用药。 二、临床超说明书用药的原则 （一）为保障病人安全，临床用药原则上不得超出药品说明书规定的范围，即不得超说明书用药。 （二）在临床工作中，特殊情况需超说明书用药时必须同时具备以下条件： 1、在影响病人生活质量或危及生命的情况下，无合理的可替代药品和疗法。但必须充分考虑药品不良反应、禁忌证、注意事项，权衡病人获得的利益大于可能出现的风险，保证该用法是最佳方案。 2、用药目的必须仅仅是为了病人的利益，而不是试验研究。 3、超说明书用药应当有必要的科学依据、会诊意见、充分的临床实践和相关文献、研究报道。 4、病人知情同意，并签署知情同意书。 三、超说明书用药的审批流程 1、临床确需超说明书用药时，对病人要实行告知并签署知情同意书。医师应充分告知病人用药方案、治疗步骤、预后情况及可能出现的风险，签署知情同意书后方可进入审批程序经批准后使用。签署的知情同意书留存使用科室。 2、超说明书用药时需由医师提出用药申请，并提供权威的文献依据（如治疗指南、专家共识、循证医学证据等），由临床科室主任签字，报院药事管理与药物治疗学委员会及伦理委员会审核同意后，报医务处备案。 四、超说明书用药的使用与调剂 1、药师在审核处方或医嘱时，应以药品说明书为依据，严格按药品说明书
超说明书用药管理规定 申请表
超说明书用药管理规定 为了进一步规范临床合理用药，降低医患纠纷风险，维护患者用药安全，结合我院实际情况，制定本制度。 一、超药品说明书用药的定义： 是指药品使用的适应症、给药方法或剂量不在药品监督管理部门批准的说明书之内的用药。超药品说明书用药的具体含义包括给药剂量、适应人群、适应症或给药途径等与药品说明书不同的用药。 二、临床超说明书用药的管理原则： （一）为保障病人安全，临床用药原则上不得超出药品说明书规定的范围，即不得超说明书用药。 （二）特殊情况需超说明书用药时必须同时具备以下条件： 1、在影响病人生活质量或危及生命的情况下，无合理的可替代药品和疗法。但必须充分考虑药品不良反应、禁忌证、注意事项，权衡病人获得的利益大于可能出现的风险，保证该用法是最佳方案。 2、用药目的必须仅仅是为了病人的治疗，而不是试验研究。 3、有合理的、确凿的循证医学证据，如有充分的文献报道、循证医学研究结果、多年临床实践证明及申请扩大药品适应症的研究结果等。 4、病人知情同意，并签署知情同意书。 三、超说明书用药的审批流程： 1、临床确需超说明书用药时，对病人要实行告知并签署《知情同意书》。医师应充分告知病人用药方案、治疗步骤、预后情况及可能出现的风险，签署知情同意书后方可进入审批程序经批准后使用。签署的知情同意书一式两份，一份给病人，一份使用科室留存。 2、超说明书用药时需由医师提出用药申请，并提供权威的循证医学依据，由临床科室主任签字，报医务科及药事管理与药物治疗学委员会批准同意。 四、超说明书用药的使用与调剂： 1、超说明书用药必须开具处方。 2、药师在审核处方或医嘱时，首先应对药品说明书有深入、细致、透彻地了解，并以药品说明书为依据，严格按药品说明书规范调剂药品，规避用药风险，确保调剂行为的安全及患者的用药安全。 3、药师调剂超说明书用药时，需认真核对知情同意书及处方，确认无误后方可调剂。
图书馆管理系统使用说明书
图书馆管理系统使用说明书 配置源程序 附加数据库SQL Server 2000 （1）将TM\05\Database文件夹中的扩展名为db_library_Data.MDF和db_library_Log.LDF的两个文件拷贝到SQL Server安装路径下的Data文件夹中。 （2）打开SQL Server 2000中的“企业管理器”，然后展开本地服务器，在“数据库”数据项上单击鼠标右键，在弹出的快捷菜单中选择“所有任务”/“附加数据库”菜单项。 （3）将弹出“附加数据库”对话框，在该对话框中单击【】按钮，选择所要附加数据库的db_library_Data.MDF文件，单击【确定】按钮，即可完成数据库的附加操作。 发布与运行 （1）将光盘\TM\05\libraryManager文件夹拷贝到MyEclipse的工作空间中。 （2）启动MyEclipse。 （3）选择“文件”/“导入”菜单项，展开“常规”节点，选择“现有项目到工作空间中”子节点，如图1.1所示。 图1.1 “导入”窗口 （4）单击【下一步】按钮，单击【浏览】按钮，选择程序所在目录，然后勾选“将项目复制到工作空间中”复选框，如图1.2所示。
图1.2 “导入”窗口 （5）单击【完成】按钮。 （6）在项目上单击鼠标右键，依次选择“新建”/“文件夹”命令，新建一个“lib”文件夹，然后，将SQL Server 2000数据库驱动文件“msbase.jar、mssqlserver.jar、msutil.jar”拷到该文件夹中。在该文件上单击鼠标右键，选择“构建路径”/“添加至构建路径”命令。 （7）在导入工程的src文件中，找到可执行的主类，在该类上单击鼠标右键，选择“运行方式”/“Java应用程序”项，如图1.3所示，完成程序配置
超说明书用药规定
超说明书用药规定 1 2020年4月19日
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CSCI详细设计说明书模板
文档编号： 项目名称 XXXX CSCI详细设计说明书 单位名称 XXXX年X月
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1 范围 1.1 标识 1.2 CSCI 概述 1.3 文档概述 2 引用的文档 3 CSCI 设计 3.1 CSCI结构 3.2 CSCI运行组织 3.3 CSCI性能要求 3.4 CSCI设计限制和约束 3.5 CSCI测试计划 4 CSC 设计 4.x CSC的名称和唯一标识符 4.x.y 下一级CSC的名称和唯一标识符 5 CSCI数据说明 5.1 CSCI内部数据元素 5.2 CSCI外部接口数据元素 6 CSCI数据文件 6.1 CSC和CSU数据文件的交叉引用 6.x数据文件名和唯一标识符 7 需求可追踪性
1.1 标识 【系统背景】 系统标识符：（系统标识符） 系统名称：（系统名称） 缩写：给出系统的缩写 【适用的CSCI】 标识符：（CSCI标识符） 名称：（CSCI名称） 缩写：给出CSCI的缩写 1.2 CSCI 概述 【系统功能概述】 简要描述本系统的功能。 【CSCI功能概述】 （给出CSCI在需求规格说明书中对应的需求规格标识号的引用）。 如有必要可用图示表示本CSCI在系统中的位置（顶层系统结构图）。1.3 文档概述 【用途】 本文档用于描述在进行CSCI详细设计中每个阶段的设计结果，提供CSCI 的详细设计说明书。 【内容】 本文档的主题内容如下： 描述CSCI的功能和作用； 定义CSCI的结构（用一组CSC，以及这些CSC之间的接口关系，定义CSC 的名称，标示符，分配的需求集）； 定义CSCI设计限制； 定义CSCI资源使用设计； 定义CSCI每个CSC以及CSU的详细设计。 描述每个CSC可追溯的需求规格和接口规格说明。
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重要性：超药品说明书用药现象的存在具有一定的合理性和必要性，但是超说明书用药有可能没有大量临床研究数据支持，也没有获得药品监管部门批准，因此必然存在一定的风险，且药品说明书具有法律效力，超药品说明书用药不受法律保护，超说明书用药导致不良后果的，医生和药师要承担相应法律责任。 《处方管理办法》第五章规定：药师应按照药品说明书或者处方用法，进行用药交代与指导。药师应当对处方用药适宜性进行审核，审核内容包括处方用药与临床诊断的相符性、剂量用法的正确性、其他用药不适宜情况等。药师经处方审核后，认为存在用药不适宜时，应当告之处方医师，请其确认或者重新开具处方，药师发现严重不合理用药或者用药错误，应当拒绝调剂。 药师在审核处方或医嘱时，首先应对药品说明书有深入、细致、透彻地了解，并以药品说明书为依据，严格按药品说明书规范调剂药品，规避用药风险，确保调剂行为的安全及患者的用药安全。 当临床医生因医疗创新确需要超药品说明书用药时，应提供权威的文献依据，并经药事管理与药物治疗学委员会审核同意，报医务科备案，使用时与患者签署知情同意书。药师在审核和调剂超药品说明书用药处方或医嘱时，严格依据《知情同意书》和医务科备案方能调剂药品。
2014超说明书用药专家共识
DOI：10.3760／cma.j.issn.1008-5734.2015.02.011 通信作者：陆进，中日友好医院药学部，Email：lujin07091＠sina. com；王少华，青岛市立医院药剂科，Email：wangsh5668＠https://www.wendangku.net/doc/7a8260788.html, ·指南与共识· 超说明书用药专家共识 中国药理学会治疗药物监测研究专业委员会药品风险管理学组 超说明书用药又称“药品说明书外用法”、“药品未注册用法”，是指药品使用的适应证、剂量、疗程、途径或人群等未在药品监督管理部门批准的药品说明书记载范围内的用法。临床药物治疗中，超说明书用药普遍存在。在美国，有21％已批准药物存在超说明书用药情况；其中，在成人用药中占7.5％~40％，在儿科用药中占50％~90％［1］。一项针对欧洲5国儿科病房用药的调查发现，46％的处方中存在超说明书适应证用药的情况［2］。另一项针对英国利物浦妇女医院17695份用药医嘱的研究显示，该院孕妇用药中有84％的药品品种和75％的用药医嘱存在超说明书用药情况；58％的药品品种和55％的医嘱用药属于孕妇慎用或禁用，其中超说明书用药分别有16％的药品品种和10％的医嘱用药属于食品和药品管理局（FDA）高危药品目录中药品［3］。超说明书用药在各个治疗领域广泛存在，由此引发了药品安全性、有效性、医疗责任和伦理学等一系列问题，有必要对其进行规范。 1 国内外超说明书用药相关立法情况 1.1 国外超说明书用药相关立法情况 美国、德国、意大利、荷兰、新西兰、印度和日本已有超说明书用药相关立法，除印度禁止超说明书用药外，其余6国均允许合理的超说明书用药。美国、英国、德国、意大利、荷兰、澳大利亚、新西兰、中国、日本和南非等10个国家的政府部门或学术组织发布了与超说明书用药相关的指南或建议［4］。在美国，FDA明确表示，“不强迫医生必须完全遵守官方批准的药品说明书用法”［5］。美国权威的指导超说明书用药资料如American Medical Association：Drug Evaluations、Us Pharmacopoeia：Drug Information和American Hospital Formulary Service：Drug Information，收录了说明书用药顾问委员会认可以及医疗专家推荐的广泛应用于临床的“说明书用法（labeled uses）”和“说明书之外的用法（off-labeled uses）”，并且定期 修改和更新。其中美国药典委员会定期更新的Drug Information，由美国药典委员会顾问小组根据当前的文献资料、临床实践中的用法及合理用药等知识，将“药品说明书用法”和“说明书之外的用法”列为“已接受的用法”，而“不合适的用法（inappropriate uses）”、“未被验证的用法（unproveduses）”及“过时的用法（obsolete uses）”等，则被列入“不可接受的用法（unaccepted uses）”。美国的一些学术团体致力于为超说明书用药寻找循证医学证据，用以指导临床医师合理使用药物［6-7］。在英国，国家医疗服务体系（National Health Service，NHS）制定了《NHS未批准及超标签用药指南》，该指南为那些未获准进入英国市场的药品以及药品的超说明书使用提供指导性方针、操作程序及参照标准。 1.2 我国超说明书用药现状及立法情况 目前，我国虽然尚无全国范围内超说明书用药情况的调查数据，但超说明书用药现象非常普遍［8-10］。虽然相关政府部门先后制订了《药品管理法》《医疗机构药事管理规定》《处方管理办法》《药品不良反应报告和监测管理办法》等多部规范药品使用的法规，但迄今尚无法律法规明确对“超说明书用药”这一行为进行规定，且《侵权责任法》《执业医师法》和《药品管理法》中涉及的相关条款原则上都不支持超说明书用药。 根据《三级综合医院评审标准实施细则（2011年版）》要求，各医疗机构需建立超说明书用药管理的规定与程序但在执行过程中有些超说明书用药是根据诊疗指南的推荐或有较充分的临床证据，有些则是缺乏相关证据的盲目应用。国内对超说明书用药缺乏统一的管理，这也是造成医疗纠纷的重要原因。 超说明书用药的风险远高于按说明书用药，而导致超说明书用药现象的根本原因是药品说明书的更新滞后于临床实践的发展。新药批准时往往基于有限的临床数据，而药品上市后经过临床实践会有很多新的发现和经验。由于更新药品说明书内容的审批过程复杂，制药公司需要花费大量时间、消耗巨额费用，才能完成符合注册要求的临床研究证据，造
小型超市管理系统详细设计说明书
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2014年5月 文档名称：详细设计规格说明书 项目名称：小型超市挂管理系统 项目负责人：张亚飞 编写 TEST _____年_____月_____日 校对所有小组成员 _____年_____月_____日 审核所有小组成员 _____年_____月_____日 批准 XXX _____年_____月_____日 开发单位__________________________________________ 组员：TEST1 TEST2 TEST3
目录 编写目的................................................. 错误!未定义书签。项目背景................................................. 错误!未定义书签。定义..................................................... 错误!未定义书签。参考资料................................................. 错误!未定义书签。需求概述................................................. 错误!未定义书签。软件结构................................................. 错误!未定义书签。 软件结构框架图 ....................................... 错误!未定义书签。登录模块................................................. 错误!未定义书签。 功能流程图 ........................................... 错误!未定义书签。 功能描述............................................. 错误!未定义书签。 （1）功能类型 .................................... 错误!未定义书签。 （2）功能描述 .................................... 错误!未定义书签。 （3）使用权限 .................................... 错误!未定义书签。 界面描述............................................. 错误!未定义书签。 （1）界面草图 .................................... 错误!未定义书签。 （2）界面要求 .................................... 错误!未定义书签。收银人员模块............................................. 错误!未定义书签。
超说明书用药管理规定(试行)
超说明书用药管理规定（试行） 为了规我院医师处方行为，强化合理用药意识、知识和行为，最大限度减少药源性损害，提高临床药物治疗水平，减少患者用药风险，避免医疗纠纷，实现对患者治疗的利益最大化，基于目前超说明书用药现状，制定本规定，在医疗活动中实施并逐步完善。 一、超说明书用药（Off-label use）系指临床在应用该药品时，超过了国家食品药品监督管理局（SFDA）对该药品的许可容，包括未批准的适应症、未批准的适应年龄组、未批准的用药途径、用法和剂量等。 二、禁止未经SFDA批准，以试验研究为目的超说明书用药。 三、各临床科室凡有超说明书用药，均需填报超说明书用药申报表（申报表见附件1），注明超说明书容，提交使用依据（附电子版或纸质资料）等，电子版发qyysgl126.，申报表提交医院药事管理与药物治疗学委员会办公室。 四、医院药事管理与药物治疗学委员会组织有关专家对各临床科室超说明书用药提请的合理性进行论证并确定分级围。 五、论证须有循证医学证据支持，或者以国家(或专业学会/协会)发布的治疗指南、诊疗规等为依据。 六、超说明书用药通过论证后，须经医院药事管理与药物治疗学委员会和医院伦理委员会审议批准，可在临床使用中执行。 七、医师不得使用未经医院批准的超说明书用药。若违规使用，发生医疗差错、纠纷、事故，将按医院有关规定处理。 八、药师应严格审核处方，对未经医院批准的超说明书用药进行干预。 九、医院批准的超说明书用药，分为A级的，必须取得患者或家属或监护人的知情同意，告知接受超说明书用药的必要性、可能的获益和可能的风险，并签署知情同意书（知情同意书见附件4）；分为B级的，需要有告知患者或家属或监护人的记录；分为C级的，需要口头告知患者或家属或监护人。 十、所有经医院批准的超说明书用药，都必须有明确的用药剂量、用药方法、用药疗程和相关记录。超说明书用药中出现任何的不良事件都应该及时上报，填写不良反应报告表，提交医院不良反应监测管理小组。
超说明书用药管理规定
超说明书用药管理规定 为加强医院药事管理工作，促进临床合理用药保障临床用药的安全性、有效性、合理性及药师自身安全，避免不必要的纠纷，依据《中华人民共和国药品管理法》（主席令第45号）、《处方管理办法》（卫生部令第53号）、《医疗机构药事管理规定》、《药品说明书和标签管理规定》等药政法规，结合我院实际情况，特制定本规定。 一、超说明书用药是指临床实际使用药品的适应证、给药方法或剂量不在具有法律效力的说明书之内的用法，包括年龄、给药剂量、适应人群、适应证、用药方法或给药途径等与药品说明书中的用法不同的情况，又称超范围用药、药品未注册用药或药品说明书之外的用法。 二、为保障患者安全，临床用药原则上不得超出药品说明书规定的范围，即不得超说明书用药。特殊情况下需超说明书用药时必须同时具备以下条件: （一）在影响病人生活质量或危及生命的情况下，无合理的可替代药品和疗法。但必须充分考虑药品不良反应、禁忌证、注意事项，权衡病人获得的利益大于可能出现的风险，保证该用法是最佳方案。 （二）用药目的必须仅仅是为了病人的利益而不是试验研究或其他关乎医师自身利益的情况超说明书用药。超说明书用药必须保证利益大于可能出现的风险。 （三）有确凿循证医学证据。
（四）病人知情同意，并签署知情同意书。 三、超药品说明书用药现象的存在具有一定的合理性和必要性，但是超说明书用药涉及医疗责任、伦理学、医保报销以及药品安全性和有效性等一系列问题，可能没有大量临床研究数据支持，也没有获得药品监管部门批准，且药品说明书具有法律效力，超药品说明书用药不受法律保护，因此存在一定的风险，超说明书用药导致不良后果的，医师和药师要共同承担相应的法律责任。 四、《处方管理办法》第五章规定:药师应按照药品说明书或者处方用法，进行用药交代与指导。药师应当对处方用药适宜性进行审核，审核内容包括处方用药与临床诊断的相符性、剂量用法的正确性、其他用药不适宜情况等。药师经处方审核后，认为存在用药不适宜时，应当告知处方医师，请其确认或者重新开具处方，药师发现严重不合理用药或者用药错误，应当拒绝调剂。 五、药师在审核处方或医嘱时，首先应对药品说明书有深入、细致、透彻地了解，并以药品说明书为依据，严格按药品说明书规范调剂药品规避用药风险，确保调剂行为的安全及患者的用药安全。 六、当临床医生因临床治疗或医疗创新确需要超药品说明书用药时，应提供权威的文献依据，由所在科室科主任对该超说明书用药的相关文献资料等进行总结和评价，规范填写《超说明书用药申请表》（附件1，一式两份），上报医务部。由医务部组织药事管理与药物治疗学委员会专家进行评价和讨论。对于证据充分的，在医务部备案后，方可使用。备案材料同时在药学部留存，作为药师审核与点评处