Nevirapine

Iupac Name：11-cyclopropyl-4-methyl-5H-dipyrido[2,3-e:2',3'-f][1,4]diazepin-6-one

Molecular Weight：266.304

Modify Date.: 2022-11-22 16:55

Introduction: Nevirapine and its analogues exhibit antiretroviral effect against azothymidine-resistant HIV strains.Nevirapine in combination with ZDV and ddI produced approximately 18% higher CD4 cell counts and adecrease in viral load compared with patients who took ZDV and ddI. Nevirapine is recommended withnucleosides for patients infected with HIV-1 who have experienced clinical or immunologic deterioration.The significant side effects of nevirapine are liver dysfunction and skin rashes. View more+

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1. Names and Identifiers

1.1 Name: Nevirapine
1.2 Synonyms: 11-Cyclopropyl-4-methyl-5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one 11-cyclopropyl-4-methyl-5H-dipyrido[2,3-e:2',3'-f][1,4]diazepin-6-one 11-Cyclopropyl-4-Methyl-5H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6(11H)-one 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one 6H-Dipyrido[2,3-b:3',2'-e][1,4]diazepin-6-one, 11-cyclopropyl-5,11-dihydro-4-Methyl- 6H-DIPYRIDO[3,2-B:2',3'-E][1,4]DIAZEPIN-6-ONE, 11-CYCLOPROPYL-5,11-DIHYDRO-4-METHYL- AIDS005653 BI-RG-587 & CD4-IgG D00435 MFCD00866928 MLS00008458 N11-Cyclopropyl-4-methyl-5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e]-[1,4]diazepin-6-one & CD4-immunoadhesin Viramune

1.3 CAS No.: 129618-40-2

1.4 CID: 4463

1.5 EINECS(EC#): 603-345-0

1.6 Molecular Formula: C15H14N4O (isomer)

1.7 Inchi: InChI=1S/C15H14N4O/c1-9-6-8-17-14-12(9)18-15(20)11-3-2-7-16-13(11)19(14)10-4-5-10/h2-3,6-8,10H,4-5H2,1H3,(H,18,20)

1.8 InChkey: NQDJXKOVJZTUJA-UHFFFAOYSA-N

1.9 Canonical Smiles: CC1=C2C(=NC=C1)N(C3=C(C=CC=N3)C(=O)N2)C4CC4

1.10 Isomers Smiles: CC1=C2C(=NC=C1)N(C3=C(C=CC=N3)C(=O)N2)C4CC4

2. Properties

2.1 Density: 1.351

2.1 Melting point: 247℃

2.1 Boiling point: 415.4 °C at 760 mmHg

2.1 Refractive index: 1.671

2.1 Flash Point: 205 °C

2.1 Precise Quality: 266.11700

2.1 PSA: 63.57000

2.1 logP: 2.47830

2.1 Solubility: In water, 100 mg/l @ neutral pH

2.2 Appearance: white to tan

2.3 Storage: -20°C Freezer

2.4 Chemical Properties: Crystalline Solid

2.5 Color/Form: Crystals from pyridine and water

2.6 Physical: Solid

2.7 pKa: 2.8(at 25℃)

2.8 Water Solubility: DMSO: ≥22mg/mL

2.9 StorageTemp: 2-8°C

3. Use and Manufacturing

3.1 Definition: ChEBI: A dipyridodiazepine that is 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine which is substituted by methyl, oxo, and cyclopropyl groups at positions 4, 6, and 11, respectively. A non-nucleoside reverse trnscriptase inhibitor with activity against HIV-1, it is used in combination with other antiretrovirals for the treatment of HIV infection.

3.2 General Description: Nevirapine (Viramune) is more than 90% absorbed by theoral route and is widely distributed throughout the body. Itdistributes well into breast milk and crosses the placenta.Transplacental concentrations are about 50% those ofserum. The drug is extensively transformed by cytochromeP450 (CYP) to inactive hydroxylated metabolites; it mayundergo enterohepatic recycling.

3.3 GHS Classification: Signal: Warning
GHS Hazard Statements
Aggregated GHS information provided by 14 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H302 (28.57%): Harmful if swallowed [Warning Acute toxicity, oral]
H412 (92.86%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P264, P270, P273, P301+P312, P330, and P501

3.4 Methods of Manufacturing: K.D. Hargrave et al; EP 429987 (1991 to Boehringer, Ing; Thomae); K.D. Hargrave et al; US 5366972 (1994 to Boehringer, Ing.)

3.5 Usage: amyloidosis therapy

4. Safety and Handling

4.1 Hazard Codes: Xi

4.1 Risk Statements: R36/37/38

4.1 Safety Statements: 26-36-37/39

4.1 Exposure Standards and Regulations: The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products incl nevirapine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

4.2 Packing Group: III

4.2 Octanol/Water Partition Coefficient: log Kow = 3.89 /Estimated/ [Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995)] PubMed Abstract

4.3 Hazard Class: 6.1

4.3 Hazard Declaration: H302

4.3 DisposalMethods: SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

4.4 RIDADR: OTH

4.4 Caution Statement: P264, P270, P273, P301+P312, P330, P501

4.4 Formulations/Preparations: Nevirapine hemihydrate: Oral: Suspension, 50 mg (of nevirapine) per 5 ml, Viramune (with parabens), Boehringer Ingelheim /Nevirapine hemihydrate/
Oral: Tablets 200 mg, Viramune (with povidone;scored) Boehringer Ingelheim

4.5 WGK Germany: 3

4.5 RTECS: JM5562500

4.5 Safety: Hazard Codes:?Xi
Risk Statements: 36/37/38?
R36/37/38:Irritating to eyes, respiratory system and skin.
Safety Statements: 26-36-37/39
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
S36:Wear suitable protective clothing.?
S37/39:Wear suitable gloves and eye/face protection.

4.6 Specification: ?Nevirapine , its cas register number is 129618-40-2. It also can be called?Viramune ; 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one ; 6H-Dipyrido(3,2-b:2',3'-e)(1,4)diazepin-6-one, 11-cyclopropyl-5,11-dihydro-4-methyl- .It is a?crystalline solid.?It has also been tested in trials in Africa, some of which have been highly controversial.

4.7 Toxicity

Organism	Test Type	Route	Reported Dose (Normalized Dose)	Effect	Source
dog	LD	oral	> 3200mg/kg (3200mg/kg)	?	Gekkan Yakuji. Pharmaceuticals Monthly. Vol. 41, Pg. 2209, 1999.
rat	LDLo	oral	400mg/kg (400mg/kg)	?	Gekkan Yakuji. Pharmaceuticals Monthly. Vol. 41, Pg. 2209, 1999.

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5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Hazardous to the aquatic environment, long-term (Chronic) - Category Chronic 3

2.2 GHS label elements, including precautionary statements

Pictogram(s)	No symbol.
Signal word	No signal word.
Hazard statement(s)	H412 Harmful to aquatic life with long lasting effects
Precautionary statement(s)
Prevention	P273 Avoid release to the environment.
Response	none
Storage	none
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

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6. Synthesis Route

129618-40-2Total: 10 Synthesis Route

2942-59-8 553 Suppliers

129618-40-2 241 Suppliers

Literatures:
Journal of Heterocyclic Chemistry, , vol. 30, # 3 p. 771 - 779
Yield: null

49609-84-9 122 Suppliers

129618-40-2 241 Suppliers

Literatures:
Journal of Heterocyclic Chemistry, , vol. 30, # 3 p. 771 - 779
Yield: null

23056-39-5 156 Suppliers

129618-40-2 241 Suppliers

Literatures:
Journal of Heterocyclic Chemistry, , vol. 30, # 3 p. 771 - 779
Yield: null

View all

7. Precursor and Product

precursor:

49609-84-9

1634-04-4

765-30-0

133627-47-1

133627-46-0

135575-99-4

162709-30-0

2942-59-8

133627-45-9

23056-39-5

product :

284686-15-3

284686-16-4

1350539-32-0

639807-18-4

8. Other Information

8.0 Target: Value

8.1 Description: Nevirapine and its analogues exhibit antiretroviral effect against azothymidine-resistant HIV strains. Nevirapine in combination with ZDV and ddI produced approximately 18% higher CD4 cell counts and a decrease in viral load compared with patients who took ZDV and ddI. Nevirapine is recommended with nucleosides for patients infected with HIV-1 who have experienced clinical or immunologic deterioration. The significant side effects of nevirapine are liver dysfunction and skin rashes.

8.2 Originator: Neve,Le Sante,India

8.3 Indications: Nevirapine (Viramune) is approved for the treatment of HIV infection in adults and children as part of a combination therapy. During the first 12 weeks of treatment, patients must be closely monitored for the development of potentially fatal hepatic toxicity (i.e., hepatitis, hepatic necrosis, and hepatic failure) and skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions). Although these toxicities are rare, common side effects include mild to moderate rash, fever, nausea, fatigue, headache, and elevated liver enzymes.

8.4 Manufacturing Process: There are 3 ways for preparing of nevirapine.
117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, 23.3 kg of calcium oxide and 59.4 kg of cyclopropylamine (molar ratio: 1:1:2.5) are heated to between 135° and 145°C in 235 L of diglyme (diethylene glycoldimethylether) in a 500 L VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20°-30°C and filtered. The filter cake is washed with 58.8 L of diglyme. The filtrates are combined and initially 200 L of solvent is distilled off. The residue is then diluted with a further 117.5 L of diglyme. The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 L of diglyme, heated to 130°C. The storage vessel and conduits are rinsed with a further 55.8 L of diglyme, and the mixture is stirred at a temperature of between 130° and 140°C for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470 L of water. After cooling to a temperature of about 25°C, 235.0 L of cyclohexane and 57.11 of glacial acetic acid are added to the reaction mixture. The mixture is then stirred for about 1 hour at temperature of 10° to 25°C. The resultant suspension is centrifuged and the centrifuged material is then washed with 235.0 L of methyl-tertbutylether and subsequently with 353.5 L of water and finally with 235 L of ethanol. In this way, after drying, 92.5 kg (83.5% of theory) of 11- cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6- one (nevirapine) is isolated.
117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, 46.7 kg of calcium oxide and 47.5 kg of cyclopropylamine (molar ratio: 1:2:2) are heated to 135° to 145°C in 235 L of diglyme (diethylene glycol dimethylether) in a 500 L VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30°C and filtered. The filter cake is washed with 58.8 L of diglyme. The filtrates are combined and about 188 L of solvent is distilled off. The residue is then diluted with a further 117.5 L of diglyme. Over a period of 20 to 40 minutes, the resultant diluted solution is added to a suspension of 45.0 kg of 60% sodium hydride in 352.5 L of diglyme, heated to 130°C. The storage vessel and conduits are rinsed with a further 55.8 L of diglyme and the mixture is stirred at a temperature of 130° to 140°C for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470.0 L of water. The reaction mixture is cooled to a temperature of about 25°C and 235.0 L of cyclohexane and 57.1 L of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10o to 25°C. The resultant suspension is centrifuged and the centrifuged material is washed with 235.0 L of methyl tert-butylether, followed by 353.5 L of water and finally with 235 L of ethanol. In this way, after drying, 90.6 kg (81.7% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido-[3,2-b:2',3'- e][1,4]diazepin-6-one (nevirapine) is isolated.
287.2 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide, 57.0 kg of calcium oxide and 87.1 kg of cyclopropylamine (molar ratio: 1:1:1.5) are heated in 574 L of diglyme (diethylene glycol-dimethylether) to 135°-145°C for about 30 minutes in a 1200 L VA stirring apparatus. This produces a pressure of 1.2-1.5 bar and about 50% of the starting material is reacted. To this mixture, over about 30 minutes at 135°-145°C, a further 58.1 kg of cyclopropylamine is added producing a pressure of 3.0-3.5 bar, and another 25% of the starting material is reacted. The mixture is then kept at 135°-145°C for a period of 5 to 6 hours. The reaction mixture is then cooled to a temperature of 20° to 30°C and filtered. The filter cake is washed with 144 L of diglyme. The filtrates are combined and 400 L of solvent is distilled off. The residue is then diluted with a further 287 L of diglyme. Over 20-40 minutes, the resultant diluted solution is added to a suspension of 110 kg of 60% sodium hydride in 862 L of diglyme, heated to 130°C. The storage vessel and conduits are rinsed with a further 144 L of diglyme and the mixture is stirred at a temperature of 130° to 140°C for another 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 1150 L of water. After the reaction mixture has been cooled to a temperature of about 25°C, 575 L of cyclohexane and 147 L of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10°-25°C. The resultant suspension is centrifuged and the centrifuged material is then washed with 575 L of methyl-tert-butylether, followed by 862 L of water and finally with 575 L of ethanol. In this way, after drying, 225 kg (83.0% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl- 6H-dipyrido[3,2-b :2',3'-e][1,4 ]diazepin-6-one (nevirapine) is obtained.

8.5 Brand name: Viramune (Boehringer Ingelheim);Nevimune.

8.6 Acquired resistance: One or more changes within the HIV reverse transcriptase at amino acid positions 100, 103, 106, 108, 181, 188 and 190 are associated with resistance. These point mutations have also been implicated, either alone or in combination, in HIV resistance to other non-nucleoside reverse transcriptase inhibitors.

8.7 General Description: Nevirapine (Viramune) is more than 90% absorbed by theoral route and is widely distributed throughout the body. Itdistributes well into breast milk and crosses the placenta.Transplacental concentrations are about 50% those ofserum. The drug is extensively transformed by cytochromeP450 (CYP) to inactive hydroxylated metabolites; it mayundergo enterohepatic recycling.

8.8 Pharmaceutical Applications: A synthetic heterocyclic compound formulated for oral use as anhydrous compound or as the hemihydrate in a liquid oral suspension.

8.9 Biochem/physiol Actions: Nevirapine is an allosteric, non-nucleoside inhibitor of HIV reverse transcriptase (NNRTI). The Ki for inhibition of wild-type RT by Nevirapine is 200 nM.

8.10 Mechanism of action: Nevirapine is a dipyridodiazepinone derivative that binds directly to RT . Thus, it blocks RNA- and DNA-dependent polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphate. The HIV-2 RT and human DNA polymerases are not inhibited by nevirapine. The 50% inhibitory concentration ranged within 10 to 100 nM against HIV-1.

8.11 Storage Conditions: K.D. Hargrave et al; EP 429987 (1991 to Boehringer, Ing; Thomae); K.D. Hargrave et al; US 5366972 (1994 to Boehringer, Ing.)

8.12 Henrys Law Constant: Henry's Law constant = 3.3X10-17 atm-cu m/mol @ 25 °C /Estimated/

8.13 Dissociation Constants: pKa = 2.8

8.14 Experimental Properties: Hydroxyl radical reaction rate constant = 6.4X10-11 cu cm/molec-sec @ 25 °C /Estimated/

8.15 Disposal Methods: SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

8.16 FDA Requirements: The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products incl nevirapine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

8.17 Interactions: Caution is required when nevirapine is concurrently administered with a protease inhibitor, as the plasma concentrations of the protease inhibitors may be reduced to subtherapeutic concentrations due to increased hepatic metabolism by nevirapine.|Concurrent use of nevirapine with cimetidine may elevate steady-state nevirapine trough concentrations; dosage adjustment may be necessary.|The AUC values of /estrogen-containing/ oral contraceptives are reduced in the presence of nevirapine; therefore, oral contraceptives should not be used as the primary means of contraception when nevirapine is prescribed to women of childbearing potential.|Concurrent use /of ketoconazole/ with nevirapine results in significantly reduced plasma concentrations of ketoconazole and modest increase in plasma concentrations of nevirapine; concurrent use is not recommended.|For more Interactions (Complete) data for NEVIRAPINE (10 total), please visit the HSDB record page.

8.18 Livertox Summary: Nevirapine is a nonnucleoside reverse transcriptase inhibitor used in combination with other agents in the therapy of human immunodeficiency virus (HIV) infection and the acquired immune deficiency syndrome (AIDS). Nevirapine is associated with a high rate of serum aminotransferase elevations during therapy and is a well established cause of acute, clinically apparent liver injury.

8.19 Drug Classes: Antiviral Agents

8.20 Therapeutic Uses: Nevirapine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection. Drug-resistant HIV emerges rapidly and uniformly when nevirapine is administered as monotherapy. Therefore, nevirapine should always be administered in combination with at least two other antiretroviral agents when it is used for the treatment of HIV-1 infection. /Included in US product labeling/|Nevirapine is indicated for the prevention of mother-to-child transmission of HIV-1 infection. /NOT included in US product labeling/|Nevirapine has been evaluated in pregnant HIV-infected women. In a landmark study performed in Uganda, a single, oral intrapartum dose of nevirapine followed by a single dose to the newborn was superior to more complicated zidovudine therapy in preventing vertical transmission. of HIV. Only 13% of nevirapine-treated women transmitted HIV compared to 21.5% of zidovudine-treated women.

8.21 Drug Warnings: Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis (e.g., transaminase elevations with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia), hepatic necrosis, and hepatic failure, have been reported in patients receiving nevirapine. Although clinical presentation varied, frequently occurring features included nonspecific prodromal signs and symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, and/or hepatomegaly, with or without initially abnormal serum transaminase concentrations; a diagnosis of hepatotoxicity should be considered even if liver function tests are initially normal or alternative diagnoses are possible. Manifestations progressed over several days to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, prolonged partial thromboplastin time, and/or eosinophilia. ... If nevirapine is discontinued because of hepatitis, it should be permanently discontinued and not reinitiated.|Hepatotoxicity has been also reported in a small number of individuals receiving nevirapine as part of a combination regimen for post-exposure prophylaxis of nosocomial or sexual HIV exposure.|Serious hepatotoxicity has been reported in individuals not infected with HIV who received multiple doses of nevirapine as part of a 2- or 3-drug regimen for postexposure prophylaxis following occupational or nonoccupational exposure to HIV. Adverse hepatic effects in these individuals have included end-stage liver failure requiring transplantation, clinical hepatitis (e.g., jaundice, fever, nausea, vomiting, abdominal pain, and/or hepatomegaly), and elevated serum ALT and AST concentrations without clinical hepatitis. ...|Severe and life-threatening skin reactions (e.g., Stevens-Johnson syndrome; toxic epidermal necrolysis; hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction), including some fatalities, have occurred in patients receiving nevirapine. ...|For more Drug Warnings (Complete) data for NEVIRAPINE (15 total), please visit the HSDB record page.

8.22 Mesh: Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS. (See all compounds classified as Anti-HIV Agents.)|Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP3A. (See all compounds classified as Cytochrome P-450 CYP3A Inducers.)|Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. (See all compounds classified as Reverse Transcriptase Inhibitors.)

8.23 Absorption: Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy subjects and adults with HIV-1 infection. The absolute bioavailability in healthy adults following a single dose administration is 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose. Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When the oral tablet is given with a high-fat meal, the extent of absorption is compared to that of the fasted-state.|Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (<5%) of the radioactivity in urine (representing <3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.|1.21 ± 0.09 L/kg [apparent volume of distribution, healthy adults, IV] Nevirapine is capable of crossing the placenta and is found in breast milk.|Nevirapine readily crosses the placenta and has been found in breast milk. The CSF-plasma ratio for nevirapine is approximately 0.45.|Nevirapine is readily (more than 90%) absorbed following oral administration in healthy or HIV-infected adults. Absolute bioavailability of nevirapine in 12 healthy adults was 93% following administration of a single 30 mg tablet or 91% following administration of an oral solution of the drug. Peak plasma nevirapine concentrations average 2 ug/ml and are attained within 4 hours after a single 200 mg dose of the dose in adults. Following multiple doses, peak plasma nevirapine concentrations appear to increase linearly in the dosage range of 200-400 mg daily. Nevirapine dosage of 400 mg daily resulted in steady-state trough plasma concentrations of 4.5 ug/ml.|Widely distributed. Nevirapine is highly lipophilic and essentially is nonionized at physiologic pH. Nevirapine readily crosses the placenta and is distributed into breast milk. Nevirapine concentrations in the cerebrospinal fluid were 45% of the concentrations in plasma, which is a ratio that is approximately equal to the fraction not bound to plasma protein.|Nevirapine crosses the placenta in humans. In a limited number of HIV-infected pregnant women who received a single 100- or 200-mg oral dose of nevirapine 0.9-10.5 hours prior to delivery, cord blood concentrations of nevirapine were 74-123% of maternal serum concentrations and peak serum concentrations of the drug in the neonates of these women averaged 862 ng/mL (range: 257-1031 ng/mL) or 925 ng/mL (range: 62-2030 ng/mL), respectively. In pregnant HIV-infected women who received a regimen of nevirapine (200 mg once daily for 2 weeks followed by 200 mg twice daily), zidovudine, and lamivudine during the second and third trimester, cord blood concentrations (at delivery) and neonatal serum concentrations (24 hours after birth) of nevirapine were 76 and 60%, respectively, of maternal serum concentrations (at delivery). These neonatal concentrations were lower than those reported in neonates whose mothers received a single nevirapine dose during labor, possibly as the result of hepatic enzyme induction in the neonate after placental transfer.|Nevirapine is distributed into human milk. Following administration of a single 100- or 200-mg dose of nevirapine to pregnant women several hours before delivery, postpartum, concentrations of the drug in milk were 25-122% of maternal serum concentrations.

8.24 Pharmacokinetics: Oral absorption: c. 93%
C_max 200 mg twice daily: c. 5.74 mg/L
C_min 200 mg twice daily: c. 2.88 mg/L
Plasma half-life: c. 36 h
Volume of distribution: c. 1.21 L/kg
Plasma protein binding: c. 60%
Absorption and distribution
Nevirapine is orally very well absorbed and widely distributed. CNS penetration is good and the semen:plasma ratio is in the range of 0.6–1. It is distributed into breast milk.
Metabolism and excretion
It is extensively metabolized by cytochrome P₄₅₀ enzymes into a number of hydroxylated intermediates that are subsequently conjugated with glucuronide. Around 81% of the dose is excreted in urine (<5% as unchanged compound) and 10% in feces. There is no significant change in the pharmacokinetics in renal impairment. It is contraindicated in patients with severe hepatic impairment; caution should be exercised in patients with moderate hepatic dysfunction.

8.25 Clinical Use: Treatment of HIV-1 infection in adults and children over 2 months old (in combination with other antiretroviral therapies)
Reduction of maternal transmission of HIV to the fetus (recommended only for use in HIV-infected treatment-naive women in labor who have had no prior HIV therapy)

8.26 Side effects: Life-threatening hepatic events, including fulminant hepatitis, have been observed in treatment-naive patients, generally within the first few weeks of treatment, but sometimes later. Approximately half the patients also develop skin rash, with or without fever or constitutional symptoms. Women with elevated CD4 counts (>250 cells/mm³) appear to be at highest risk. Men with pretreatment CD4 counts >400 cells/mm³are also at increased risk. These risks exist in the absence of underlying hepatic abnormalities and, in some cases, hepatic injury continues to progress despite discontinuation of treatment. Treatment should stop, and not be restarted, in patients with clinical evidence of hepatitis. A starting dose of 200 mg per day, with escalation to full dose if no adverse reaction occurs, reduces the frequency of reaction. Single doses given to mothers or infants for prevention of perinatal HIV infection appear safe.

8.27 Merck: 14,6490

8.28 Chemical Properties: Crystalline Solid

8.29 Uses: amyloidosis therapy

8.30 Uses: Labelled Nevirapine , a potent (IC50=84nM) and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Antiviral.;Labeled Nevirapine, intended for use as an internal standard for the quantification of Nevirapine by GC- or LC-mass spectrometry.

8.31 Uses: A potent (IC50=84nM) and selective non-nucleoside inhibitorf HIV-1 reverse transcriptase

8.32 Definition: ChEBI: A dipyridodiazepine that is 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine which is substituted by methyl, oxo, and cyclopropyl groups at positions 4, 6, and 11, respectively. A non-nucleoside reverse tr nscriptase inhibitor with activity against HIV-1, it is used in combination with other antiretrovirals for the treatment of HIV infection.

8.33 Brand name: Viramune (Boehringer Ingelheim).

8.34 Metabolism: Hepatic. In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 3A4 metabolism to several hydroxylated metabolites.|Oxidative metabolism of nevirapine in the liver by cytochrome p450 isoforms CYP34A4 and CYP2B6 produces several metabolites including 2-, 3-, 8-, and 12-hydroxynevirapine.|In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome p450 oxidative metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome p450 isozymes from the CYP3A family, although other isozymes may have a secondary role.|Nevirapine has known human metabolites that include 12-hydroxy-nevirapine, 2-Hydroxynevirapine, 3-Hydroxynevirapine, and 8-Hydroxynevirapine.

8.35 Biological Half Life: 45 hours|Approximately 45 hours after a single dose, and 25 to 30 hours following multiple dosing with 200 to 400 mg per day.

8.36 Antidote: Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

8.37 Human Toxicity Excerpts: /HUMAN EXPOSURE STUDIES/ The DRESS (drug rash with eosinophilia and systemic symptoms) syndrome is a serious condition that has been reported in association with various drugs, such as allopurinol, sulfonamides and aromatic anticonvulsants. Recently the condition has been described in HIV-infected patients taking antiretroviral agents. We report the first case, to our knowledge, of DRESS syndrome complicated by meningoencephalitis associated with nevirapine therapy.|/HUMAN EXPOSURE STUDIES/ Because most occupational HIV exposures do not result in transmission of HIV, health care providers considering prescribing post-exposure prophylaxis for exposed persons must balance the risk for HIV transmission represented by the exposure and the exposure source against the potential toxicity of the specific agent(s) used. In many circumstances, the risks associated with nevirapine as part of a post-exposure prophylaxis regimen outweigh the anticipated benefits.|/HUMAN EXPOSURE STUDIES/ Overdosage of nevirapine (800-1800 mg/daily for up to 15 days) has resulted in edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, and weight decrease; these effects subsided following discontinuance of the drug.|/HUMAN EXPOSURE STUDIES/ Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis (e.g., transaminase elevations with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia), hepatic necrosis, and hepatic failure, have been reported in patients receiving nevirapine. Although clinical presentation varied, frequently occurring features included nonspecific prodromal signs and symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, and/or hepatomegaly, with or without initially abnormal serum transaminase concentrations; a diagnosis of hepatotoxicity should be considered even if liver function tests are initially normal or alternative diagnoses are possible. Manifestations progressed over several days to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, prolonged partial thromboplastin time, and/or eosinophilia. ... If nevirapine is discontinued because of hepatitis, it should be permanently discontinued and not reinitiated.|For more Human Toxicity Excerpts (Complete) data for NEVIRAPINE (6 total), please visit the HSDB record page.

8.38 Mesh Entry Terms: BI RG 587

8.39 Formulations: Nevirapine hemihydrate: Oral: Suspension, 50 mg (of nevirapine) per 5 ml, Viramune (with parabens), Boehringer Ingelheim /Nevirapine hemihydrate/|Oral: Tablets 200 mg, Viramune (with povidone;scored) Boehringer Ingelheim

8.40 Use Classification: Human drugs -> Viramune -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human drugs -> Nevirapine Teva -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9. Computational chemical data

Molecular Weight: 266.304g/mol
Molecular Formula: C₁₅H₁₄N₄O
Compound Is Canonicalized: True
XLogP3-AA: 2
Exact Mass: 266.11676108
Monoisotopic Mass: 266.11676108
Complexity: 397
Rotatable Bond Count: 1
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 4
Topological Polar Surface Area: 58.1
Heavy Atom Count: 20
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADccBzoAAAAAAAAAAAAAAAGAAAAAAAAAAsWAAABYAAAAAB4AAAHgAQAAAADCjBmgQ/8JPIEACoAjd3dACCgCk1EiAJ2CE4dNiIYPrA3ZGUIYhohALIyeYYAQAOAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==

10. Question & Answer

Application of Nevirapine as the Non-Nucleoside Reverse Transcriptase Inhibitor Mar 24 2021
Chemical name: 11-cyclopropyl-5,11-dihydro-4-methyl-6-hydrogen-bipyridine-[3,2-b: 2,3-e][1,4]diazepine- 6-ketone Sold under the brandname in China: Nevirapine Appearance: white or off-white powder, odorless. English name: Nevirapine (NVP for short). Structural features: dipyridodiazepine. Nucleosid...

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