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Zafirlukast — (Accolate)

International Brand Names

Zuvair (India)

Drug Class Antiasthmatics; Leukotriene antagonists
Indications Asthma prophylaxis
Mechanism Leukotriene D4 and E4 receptor antagonist (LTRA)
Dosage With Qualifiers Asthma prophylaxis—20 mg PO 1 h ac or 2 h pc bid
NOTE: Hepatic dosing.

  • Contraindications —hypersensitivity to drug or class, acute asthma

  • Caution —hepatic dysfunction, systemic corticosteroid taper

Maternal Considerations There is only limited published experience with zafirlukast during pregnancy. LTRAs have a bronchodilator action and inhibit airway inflammation, resulting in a significant improvement of asthma symptoms, respiratory function, frequency of as-needed inhaled β 2 -agonists, airway inflammation, airway hyperresponsiveness, asthma exacerbations, and patients’ quality of life. Although deeply associated with pathogenesis, LTRAs alone are less effective compared with inhaled corticosteroids. Leukotriene receptor antagonists are probably safe during pregnancy but should be limited to patients for whom they are viewed essential for asthma control.
Side effects include Churg-Strauss syndrome, headache, rhinitis, N/V, diarrhea, pain, asthenia, abdominal pain, dizziness, myalgia, fever, back pain, increased hepatic transaminases, and dyspepsia.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether zafirlukast crosses the human placenta. In one report, the subjects were participants of the Organization of Teratology Information Specialists Asthma Medications in Pregnancy Study. Perinatal outcomes among 96 women who took leukotriene receptor antagonists (LTRAs) ( montelukast or zafirlukast ) were compared with women who exclusively took short-acting β-agonists (n = 122) and women without asthma (n = 346). LTRA use was not associated with an increased risk of pregnancy loss, gestational diabetes, preeclampsia, low maternal weight gain, preterm delivery, low Apgar scores, or reduced measures of birth length and head circumference in infants. The prevalence of major structural defects in the LTRA group (5.95%) was higher compared with nonasthmatic controls ( P = 0.007), but not different from the comparison group with asthma ( P = 0.524). Furthermore, the defects observed in the LTRA group did not represent a consistent pattern. These findings suggest LTRAs are not a major human teratogen. Rodent and primate studies are reassuring, revealing no evidence of teratogenicity or IUGR (unless there was maternal toxicity) despite the use of doses higher than those used clinically.
Breastfeeding Safety Zafirlukast is excreted into human breast milk with an M:P ratio of 0.2. The oral availability of zafirlukast is poor, and the relative infant dose is < 1%.
Drug Interactions Increases the t/2 and AUC of warfarin. The mean PT increased by approximately 35%. This interaction is probably due to an inhibition by zafirlukast of the CYP2C9. Monitor anticoagulant therapy closely.
Other drugs metabolized by CYP2C9 include carbamazepine, phenytoin, and tolbutamide. These combinations have not been studied.
Use with erythromycin decreases mean plasma levels of zafirlukast by approximately 40%.
Use with theophylline may decrease mean plasma levels of zafirlukast by some 30%. Rare instances of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of zafirlukast have been reported. The mechanism of the interaction is unknown.
Aspirin increases plasma levels of zafirlukast by approximately 45%.
Zafirlukast is poorly absorbed when administered with food.
References Bakhireva LN, Jones KL, Schatz M, et al. Organization of Teratology Information Specialists Collaborative Research Group. J Allergy Clin Immunol 2007; 119:618-25.
Spector SL. Ann Allergy Asthma Immunol 2001; 86:18-23.
Summary Pregnancy Category: B
Lactation Category: S (likely)

  • Zafirlukast should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • Leukotriene receptor antagonists are probably safe during pregnancy but should be limited to special circumstances, where they are viewed essential for asthma control.

  • There are alternative agents for which there is more experience regarding use during pregnancy and lactation.

Zaleplon — (Sonata)

International Brand Names

Hegon (Argentina); Hipnodem (Argentina); Noctiplon (Chile); Plenidon (Chile, Peru); Prox (Uruguay); Sonata (Mexico); Starnoc (Canada); Zaplon (India)

Drug Class Anxiolytics; Hypnotics
Indications Short-term treatment of insomnia
Mechanism Interacts with GABA/benzodiazepine receptor complex
Dosage With Qualifiers Short-term treatment of insomnia—5–10 mg PO qhs prn; onset 60 min, duration < 5 h

  • Contraindications —hypersensitivity to drug or class

  • Caution —hepatic dysfunction, history of substance abuse, pulmonary disease

Maternal Considerations The published experience with zaleplon during pregnancy is limited.
Side effects include dependency, drowsiness, amnesia, paresthesias, abnormal vision, dizziness, headache, hangover, rebound insomnia, and confusion.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether zaleplon crosses the human placenta. Data from the Swedish Medical Birth Registry (July 1, 1995 to 2007) were used to identify 1318 women with first-trimester use of zaleplon or a similar class drug. There was no evidence of teratogenic effects with zaleplon or similar agents. Rodent studies are also reassuring, revealing no evidence of teratogenicity at doses 48 × and 49 × the MHRD. However, pre- and postnatal development studies revealed increased pup stillbirth and postnatal mortality, along with decreased growth and physical development in the offspring of females treated with doses of 7 mg/kg/d or greater during the latter part of gestation and throughout lactation.
Breastfeeding Safety Small quantities of zaleplon are excreted into human breast milk. The relative infant dose is approximately 1.5% of the maternal dose. This quantity is unlikely to result in a clinically relevant level.
Drug Interactions Potentiates the CNS-impairing effects of ethanol.
Use with either imipramine or thioridazine may have additive effects on decreased alertness and impaired psychomotor performance for 2–4 h after administration.
The potent CYP3A4 inducer rifampin may reduce zaleplon C max and AUC by approximately 80%, and its use may decrease the efficacy of zaleplon. An alternative non-CYP3A4 substrate hypnotic agent may be considered in patients taking CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, and rifampin.
Cimetidine inhibits both aldehyde oxidase and CYP3A4, the primary and secondary enzymes responsible for zaleplon metabolism. Cimetidine increased the mean C max and AUC of zaleplon by 85%. As a result, an initial dose of 5 mg should be given to patients who are concomitantly being treated with cimetidine.
References Darwish M, Martin PT, Cevallos WH, et al. J Clin Pharmacol 1999; 39:670-4.
Wikner BN, Kallen B. J Psychopharmacol 2011; 31:356-9.
Summary Pregnancy Category: C
Lactation Category: S (likely)

  • Zaleplon should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

  • There are alternative agents for which there is more experience during pregnancy and lactation.

Zanamivir — (Relenza)

International Brand Names

Relenza (Argentina, Canada, Costa Rica, Dominican Republic, El Salvador, France, Germany, Guatemala, Honduras, Hong Kong, Korea, Mexico, Nicaragua, Panama)

Drug Class Antivirals
Indications Uncomplicated influenza
Mechanism Inhibits influenza neuraminidase
Dosage With Qualifiers Uncomplicated influenza—begin within 48 h of symptoms, 10 mg INH q2–4h × 2, then q12h × 5 d

  • Contraindications —hypersensitivity to drug or class, COPD, asthma, unable to use inhaler

  • Caution —unknown

Maternal Considerations Zanamivir is well tolerated during pregnancy. Pregnant women should strongly consider vaccination prior to influenza season.
Side effects include bronchospasm, nausea, dizziness, headache, bronchitis, cough, nasal symptoms, and ear/nose/throat infection.
Fetal Considerations There are no adequate reports or well-controlled studies in human fetuses. It is unknown whether zanamivir crosses the human placenta. It does cross the rodent placenta. The national registers covering maternal healthcare, births, and prescriptions in Denmark, Norway, and Sweden and the EFEMERIS database from the Haute-Garonne district in France were used to determine whether use of neuraminidase inhibitors during pregnancy was associated with adverse outcomes. Exposure to neuraminidase inhibitors was not associated with increased risks of any of the investigated neonatal outcomes, including low birth weight, low Apgar, preterm birth, SGA, stillbirth, neonatal mortality, and neonatal morbidity. There was no increased risk of birth defects overall associated with maternal exposure in the first trimester. Rodent studies are for the most part reassuring, with only minor skeletal abnormalities occurring in one strain of rat when the dose exceeded 1000 × the MRHD.
Breastfeeding Safety There is no published experience in nursing women. It is unknown whether zanamivir enters human breast milk, but its oral bioavailability is very low. It is excreted into rodent milk.
Drug Interactions No clinically relevant interactions identified.
References Dunstan HJ, Mill AC, Stephens S, et al. BJOG. 2014; 121:901-6.
Graner S, Svensson T, Beau AB, et al. BMJ 2017; 356:j629.
Summary Pregnancy Category: C
Lactation Category: S (probably)

  • Zanamivir should be used during pregnancy and lactation only if the benefit justifies the potential perinatal risk.

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