NEVIRAPINE

Drugs in Pregnancy and Lactation.

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Name: NEVIRAPINE
Class: Antiviral
Risk Factor:    CM

Fetal Risk Summary

Nevirapine is used in combination with other antiviral agents in the treatment of human immunodeficiency virus (HIV) infections. It is a nonnucleoside reverse transcriptase inhibitor. Other agents in this class include delavirdine and efavirenz.

No teratogenic effects were observed in reproductive studies with rats and rabbits (1). In rats, however, a significant decrease in fetal weight occurred at doses producing systemic levels approximately 50% higher (based on area under the plasma concentration curve comparisons) than those seen with the recommended human dose. Moreover, impaired fertility was noted in female rats at doses producing levels approximately equal to those seen with the recommended human dose (1).

Nevirapine readily crosses the human placenta to the fetus (1). In a study reported by the manufacturer, nevirapine crossed the placentas of 10 HIV type 1 (HIV-1)–infected women given a single oral dose of 100 or 200 mg a mean 5.8 hours before delivery (1). The placental transfer is consistent with the low molecular weight of approximately 266.

A study published in 1998 described the pharmacokinetics of nevirapine in 18 HIV-1–infected women who received the drug in active labor (2). In the first cohort, 10 women were treated with 100 mg or 200 mg of nevirapine, but no drug was given to their infants. On the basis of the pharmacokinetic data in the first cohort, eight additional women were given a 200-mg dose of nevirapine during active labor and their infants received a 2-mg/kg dose 48–72 hours after birth. In this latter cohort, delivery occurred a median 5.4 hours after dosing. The median cord blood nevirapine concentration was 1106 ng/mL, resulting in a median ratio of cord blood:maternal plasma of 82.9% (range 71.9%–120.2%) (2). The median calculated nevirapine concentration 7 days after birth was 215 ng/mL (range 112–275 ng/mL) (2). Maintaining the concentration above 100 ng/mL (10 times the in vitro 50% inhibitory concentration [IC50] against HIV) during labor and in the neonate during the 7 days of life was a specific goal of the study (2). No adverse effects due to nevirapine or HIV-infected infants were observed.

A 1999 study also described the pharmacokinetics of a single 200-mg dose of nevirapine given to 20 HIV-infected women during labor and to 13 of the neonates at 72 hours (3). The median cord:maternal blood ratio was 0.75. The target drug level (>100 ng/mL; 10 times the IC50) in the neonates was maintained in all infants at 7 days of age, whether or not they received nevirapine at 72 hours. No serious adverse effects attributable to nevirapine were observed (3).

The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2000, prospective data (reported to the Registry before the outcomes were known) involving 526 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (4). Nine of the newborns had congenital defects (1.7%, 95% confidence interval [CI] 0.8–3.3). There were 25 infants with birth defects among 1,256 live births with exposure anytime during pregnancy (2.0%, 95% CI 1.3–3.0). The prevalence rates for the two periods did not differ significantly, nor did they differ from the rates expected in a nonexposed population (4).

There were 162 outcomes exposed to nevirapine (57 in the 1st trimester and 105 in the 2nd and/or 3rd trimesters) either alone (1 in the 3rd trimester) or in combination with other antiretroviral agents (4). There were four infants with birth defects, three exposed in the 1st trimester and one exposed during the 2nd and/or 3rd trimesters. The specific defects and treatments were not identified. In comparing the outcomes of prospectively registered cases to the birth defects among retrospective cases (pregnancies reported after the outcomes were known), the Registry concluded that there was no pattern of anomalies to suggest a common cause (4). (See Lamivudine for required statement.) A 2000 case report described the pregnancy outcomes of two pregnant women with HIV infection who were treated with the anti-infective combination trimethoprim/sulfamethoxazole for prophylaxis against Pneumocystis carinii, concurrently with antiretroviral agents (5). One of the cases involved a 31-year-old woman who presented at 15 weeks' gestation. She was receiving trimethoprim/sulfamethoxazole, didanosine, stavudine, nevirapine, and vitamin B supplements (specific vitamins and dosage not given) that had been started before conception. A fetal ultrasound at 19 weeks' gestation revealed spina bifida and ventriculomegaly. The patient elected to terminate her pregnancy. The fetus did not have HIV infection. Defects observed at autopsy included ventriculomegaly, an Arnold-Chiari malformation, sacral spina bifida, and a lumbosacral meningomyelocele. The authors attributed the neural tube defects to the antifolate activity of trimethoprim (5).

A study published in 1999 evaluated the safety, efficacy, and perinatal transmission rates of HIV in 30 pregnant women receiving various combinations of antiretroviral agents (6). Many of the women were substance abusers. Nevirapine was used in combination with zidovudine, didanosine, and/or lamivudine in two of the women. Antiretroviral therapy was initiated at a median of 14 weeks' gestation (range preconception to 32 weeks). In spite of previous histories of extensive antiretroviral experience and of vertical transmission of HIV, combination therapy was effective in treating maternal disease and in preventing transmission to the current newborns. No adverse outcomes were noted in the two nevirapine-exposed cases (6).

A 1999 study compared the safety and efficacy of a short course of nevirapine to zidovudine for the prevention of mother-to-child transmission of HIV-1 (7). At the onset of labor, women were randomly assigned to receive either a single dose of nevirapine (200 mg) plus a single dose (2 mg/kg) to their infants 24–72 hours after birth (N=310) or zidovudine (600 mg then 300 mg every 3 hours until delivery) plus 4 mg/kg twice daily for 7 days to their infants (N=308). Nearly all (98.8%) of the women breast-fed their infants immediately after birth. Up to age 14–16 weeks, significantly fewer infants in the nevirapine group were HIV-1 infected, lowering the risk of infection or death, compared with zidovudine, by 48% (95% CI, 24–65) (7). The prevalence of maternal and infant adverse effects was similar in the two groups. In an accompanying study, the nevirapine regimen was shown to be cost-effective in various seroprevalence settings (8).

In summary, the limited human data do not allow a prediction as to the safety of nevirapine during early pregnancy even though the drug was not teratogenic in two animal species. The toxic effects on rat fertility and fetal weight gain at systemic levels at or slightly higher than those obtained in humans suggests that there is a potential for risk. Moreover, exposure of the human embryo/fetus is likely to occur because the agent, at least at term, readily crosses the human placenta. Two reviews, one in 1996 and the other in 1997, concluded that all women currently receiving antiretroviral therapy should continue to receive therapy during pregnancy and that treatment of the mother with monotherapy should be considered inadequate therapy (9,10). In 1998, the Centers for Disease Control and Prevention (CDC) made a similar recommendation that antiretroviral therapy should be continued during pregnancy, but discontinuation of all therapy during the 1st trimester was a consideration (11).

Although the study cited above (7) has shown that single doses of nevirapine administered to mothers and their infants were more effective in lowering the risk of HIV infection and death than a short course of maternal and newborn zidovudine, confirmation of these findings is required before nevirapine can be recommended for this purpose. Moreover, in utero exposure to nevirapine during the 2nd and 3rd trimesters may induce hepatic cytochrome P450 CYP3A metabolism, thereby increasing the drug's clearance in the newborn (12). Therefore, offspring of pregnant women chronically treated with nevirapine may not receive protection from HIV infection for the full 7 days observed in those not exposed to chronic dosing (12). Because the efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn are unknown, zidovudine remains the only antiretroviral agent recommended for this purpose in developed countries (9,10). A review published in 2000 reviewed seven clinical trials that have been effective in reducing perinatal transmission, five with zidovudine alone, one with zidovudine plus lamivudine, and one with nevirapine (13). Six of the trials were in less-developed countries. Prolonged use of zidovudine in the mother and infant was the most effective for preventing vertical transmission, but also the most expensive. Single-dose nevirapine (in the mother and infant) was the least expensive and the simplest regimen to administer (13).

Breast Feeding Summary

Nevirapine is excreted into human breast milk. In a study reported by the manufacturer, nevirapine was found in the breast milk of 10 women with HIV-1 infection given a single oral dose of 100 or 200 mg a mean 5.8 hours before delivery (1). In 21 HIV-infected women who had received a single 200-mg dose of nevirapine during labor, the median milk:maternal plasma ratio was 60.5% (range 25.3%–122.2%) (3). At 48 hours after birth, the median breast milk concentration was 454 ng/mL (range 219–972 ng/mL), declining to 103 ng/mL (range 50–309 ng/mL) 7 days after birth (3).

HIV-1 is transmitted in milk, and in developed countries, breast feeding is not recommended (9,10,14,15 and 16). In less-developed countries, breast feeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Zidovudine, zidovudine plus lamivudine, and nevirapine have all been shown to reduce, but not eliminate, the risk of HIV-1 transmission during breast feeding (see also Lamivudine and Zidovudine) (13).

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References

  1. Product information. Viramune. Roxane Laboratories, 2001.
  2. Mirochnick M, Fenton T, Gagnier P, Pav J, Gwynne M, Siminski S, Sperling RS, Beckerman K, Jimenez E, Yogev R, Spector SA, Sullivan JL, for the Pediatric AIDS Clinical Trials Group Protocol 250 team. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. J Infect Dis 1998;178:368–74.
  3. Musoke P, Guay LA, Bagenda D, Mirochnick M, Nakabiito C, Fleming T, Elliott T, Horton S, Dransfield K, Pav JW, Murarka A, Allen M, Fowler MG, Mofenson L, Hom D, Mmiro F, Jackson JB. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS 1999;13:479–86.
  4. The Antiretroviral Pregnancy Registry for abacavir (Ziagen), amprenavir (Agenerase, APV), delavirdine mesylate (Rescriptor), didanosine (Videx, ddl), efavirenz (Sustiva, Stocrin), indinavir (Crixivan, IDV), lamivudine (Epivir, 3TC), lamivudine/zidovudine (Combivir), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir), saquinavir (Fortovase, SQV-SGC), saquinavir mesylate (Invirase, SQV-HGC), stavudine (Zerit, d4T), zalcitabine (Hivid, ddC), zidovudine (Retrovir, ZDV). Interim Report. 1 January 1989 through 31 July 2000. 2000(December);11(No. 2):1–55.
  5. Richardson MP, Osrin D, Donaghy S, Brown NA, Hay, Sharland M. Spinal malformations in the fetuses of HIV infected women receiving combination antiretroviral therapy and co-trimoxazole. Eur J Obstet Gynecol Reprod Biol 2000;93:215–7.
  6. McGowan JP, Crane M, Wiznia AA, Blum S. Combination antiretroviral therapy in human immunodeficiency virus-infected pregnant women. Obstet Gynecol 1999;94:641–6.
  7. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795–802.
  8. Marseille E, Kahn JG, Mmiro F, Guay L, Musoke P, Fowler MG, Jackson JB. Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa. Lancet 1999;354:803–9.
  9. Carpenter CCJ, Fischi MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy for HIV infection in 1996. JAMA 1996;276:146–54.
  10. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
  11. Centers for Disease Control and Prevention. Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 1998;47:No. RR-2.
  12. Taylor GP, Lyall EGH, Back D, Ward C, Tudor-Williams G. Pharmacological implications of lengthened in-utero exposure to nevirapine. Lancet 2000;355:2134–5.
  13. Mofenson LM, McIntyre JA. Advances and research directions in the prevention of mother-to-child HIV-1 transmission. Lancet 2000;355:2237–44.
  14. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
  15. de Martino M, Tovo P-A, Pezzotti P, Galli L, Massironi E, Ruga E, Floreea F, Plebani A, Gabiano C, Zuccotti GV. HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS 1992;6:991–7.
  16. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.

Index

Q&A about Nevirapine

R K
does anyone know how I can purchase Nevirapine and get it sentto Africa I want to buy like 100 or 200 dollars?
I want to buy like 100 or 200 dollars every month and send it to doctors so they cansave some babaies anyone know which is the best way to easily save babies by getting this money in the right hands?
newusrev...
try some Canadian mail pharmaceutical companies
Amarjeet...
what is the intrasubject variability of Nevirapine in healthy volunteers? Please provide references also.?
huggz
see link....
Rohit C
How can NEVIRAPINE be synthesised?
Nevirapine is used againts AIDS. It is Non Nucleoside Reverse Transcriptase Inhibitor. How has this been synthesised by various scientists and how is it synthesised commercially?
H. Scot
From what I gather on the Internet, it is very expensive to synthesize, as several sites mentioned it...though I didn't locate any that described—in words that I would understand without days of research—how it is synthesized.

Good luck!
babs
what factors does one need to consider when trying to develop a dissolution medium for a tablet?
I wish to perform dissolution tests on some tablets e.g. Glimepiride tablets, Nevirapine tablets, Lamivudine tablets, Stavudine capsules.I want to know how the choice of dissolution medium is arrived at and what factors contribute to the choice of the medium
anza_1
aye carrumba, very tricky question here. I'll try to give it a shot.

You'll have to pick a dissolution media AND apparatus that has some sort of correlation to the medium that the tablets will be used in. For instance if the binder is highly water soluble, water may not be the best medium choice since stomach fluid is clearly not pure water.To do this you will need to have some sort of idea how quickly the tablets dissolve in-vivo (is it a quick release, or slow release, does it dissolve on contact, or is there a barrier coat?). From here you should be able to make some medium choices based on similar drugs and especially the binder in the tablet, since that is really what you are trying to dissolve. Next, select an apparatus that should go well with your expected in-vivo dissolution profile.

There is actually a fair amount of trial and error associated with this activity in industry for new drugs/binders/delivery methods. However, if you are working a generic replacement or very similar drug with a well understood binder, previous experience will be a good guide.

In fact you can go to the FDA database for some help with this:

http://www.fda.gov/cder/dmethods/FAQ.htm

They have a database of dissolution methods that may be helpful to narrow down your initial choices.
angara
what r the side effects of zidovudine ,nevirapine,...these r the drugs used in anti retro viral therapy.plz re
Fadzly
This are the HIV drugs

The side effects of zidovudine are:

headache, back pain, malaise, anorexia, constipation, nausea and vomiting, abdominal pain, join pain, chills, undigest food(dyspepsia), fatigue, jaundice(hyperbilirubinemia or yellow discolouration of skin or mucosa, insomnia, syncope,musculoskeletal pain, myalgia, and neuropathy, and also with rare complication like cardiomyopathy, breast development in man, eye oedema

mouth ulcer, dysphagia, flatulance, oral pigmentation, anaemia, hepatitis, myositis shortness of breath, hesitancy to urinate and others neurological involvement for example anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo and loss of hearing

For Nevirapine

hepatitis or liver failure, Stevens-Johnson syndrome(a syndrome that usually cause by drugs, an immune complex mediated hypersensitivity that affect the skin and mucosa leading to cell death or necrosis), toxic epidermal necrolysis, and other hypersensitivity reactions.

Other than that some rash all over the body, fever, malaise, fatigue, blisters, oral ulcer, conjunctivitis, muscle or joint pain, facial swelling, lymphnode enlargement, or renal failure.