AMPRENAVIR

Drugs in Pregnancy and Lactation.

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Name: AMPRENAVIR
Class: Antiviral
Risk Factor:    CM

Fetal Risk Summary

Amprenavir is an inhibitor of human immunodeficiency virus type 1 (HIV-1) protease (PI). Protease is an enzyme that is required for the cleavage of viral polyprotein precursors into active functional proteins found in infectious HIV. Amprenavir, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infections. Other drugs in this class are indinavir, nelfinavir, ritonavir, and saquinavir.

In reproduction studies with amprenavir, doses two times the human clinical exposure (HCE) based on AUC comparisons in male and female rats had no effect on fertility or mating (1). During embryo and fetal development, doses one-half the HCE produced thymic elongation and incomplete ossification of bones. When administered from day 7 of gestation to day 22 of lactation, a dose two times the HCE was associated with reduced body weights. However, subsequent development of the offspring, including fertility and reproductive performance, was not affected (1). In rabbits, doses up to one-twentieth the HCE were associated with abortions and minor skeletal variations resulting from deficient ossification of the femur, humerus trochlea, and humerus (1).

Amprenavir is transferred across the rat and rabbit placentas to the fetus (1). In an ex vivo human placental model, the antiviral agent also readily crossed to the fetus but with a clearance index less than abacavir. No accumulation of the drug was measured (2). The placental transfer is consistent with the relatively low molecular weight of amprenavir (about 506).

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 to one or more antiretroviral agents during the 1st trimester (3). 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 (3).

There were three outcomes that were exposed in the 1st trimester to amprenavir in combination with other antiretroviral agents (3). There were no birth defects observed in these infants. 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 (3). (See Lamivudine for required statement.) A public health advisory has been issued by the Food and Drug Administration (FDA) on the association between protease inhibitors and diabetes mellitus (4). Because pregnancy is a risk factor for hyperglycemia, there was concern that these antiviral agents would exacerbate this risk. An abstract published in 2000 described the results of a study involving 34 pregnant women treated with protease inhibitors (none with amprenavir) compared to 41 controls that evaluated the association with diabetes (5). No association between protease inhibitors and an increased incidence of gestational diabetes was found.

In summary, the near absence of human data does not allow a prediction as to the safety of amprenavir during pregnancy. However, the developmental toxicity observed in animals at doses less than the human clinical dose is a potential concern for human pregnancies. Two reviews, one in 1996 and the other in 1997, however, 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 (6,7). 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 (4). If indicated, therefore, protease inhibitors, including amprenavir, should not be withheld in pregnancy (with the possible exception of the 1st trimester) because the expected benefit to the HIV-positive mother probably outweighs the unknown risk to the fetus. However, one review suggested that during pregnancy ritonavir (see Ritonavir) was the drug of choice among the protease inhibitors (7). Pregnant women taking protease inhibitors should be monitored for hyperglycemia. The efficacy and safety of combined therapy in preventing vertical transmission of HIV to the newborn, however, are unknown, and zidovudine remains the only antiretroviral agent recommended for this purpose (6,7).

Breast Feeding Summary

No reports describing the use of amprenavir during human lactation have been located. The antiviral agent is excreted into the milk of lactating rats (1). In addition, the molecular weight (about 506) is low enough that excretion into human breast milk should be expected.

Reports on the use of amprenavir during human lactation are unlikely because the antiviral agent is used in the treatment of human immunodeficiency virus (HIV) infections. HIV-1 is transmitted in milk, and in developed countries, breast feeding is not recommended (6,7,8,9 and 10) . In developing countries, breast feeding is undertaken, despite the risk, because there are no affordable milk substitutes available. Until 1999, no studies had been published that examined the effect of any antiretroviral therapy on HIV-1 transmission in milk. In that year, a study involving zidovudine was published that measured a 38% reduction in vertical transmission of HIV-1 infection in spite of breast feeding when compared to controls (see Zidovudine).

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References

  1. Product information. Agenerase. Glaxo Wellcome, 2000.
  2. Bawdon RE. The ex vivo human placental transfer of the anti-HIV nucleoside inhibitor abacavir and the protease inhibitor amprenavir. Infect Dis Obstet Gynecol 1998;6:244–6.
  3. 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-HGV), stavudine (Zerit, d4T), zalcitabine (Hivid, ddC), zidovudine (Retrovir, ZDV). 1 January 1989 through 31 July 2000. Interim Report. 2000(December);11(No. 2):1–55.
  4. CDC 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.
  5. Fassett M, Kramer F, Stek A. Treatment with protease inhibitors in pregnancy is not associated with an increased incidence of gestational diabetes (abstract). Am J Obstet Gynecol 2000;182:S97.
  6. 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.
  7. Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997;176:478–89.
  8. Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990;33:276–89.
  9. 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.
  10. Van de Perre P. Postnatal transmission of human immunodeficiency virus type 1: the breast feeding dilemma. Am J Obstet Gynecol 1995;173:483–7.

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