Table 4.
Evidence table for use of oral benzodiazepines with hormonal contraceptives
| Author, year, funding source | Design | Study population | Exposure Psychotropic drug | Exposure Contraceptive | Outcomes | Results | Strengths | Limitations | Quality |
|---|---|---|---|---|---|---|---|---|---|
| Clinical studies for oral benzodiazepines | |||||||||
| Kroboth 1985 Upjohn Company |
Secondary outcome of parallel PK study | Women on COCs (n=19) vs not taking COCs (n=21) (matched by age, weight, smoking status) | Single oral doses of either: triazolam 0.5 mg and temazepam 30 or alprazolam 1 mg and lorazepam 2 mg, dosed 28 days apart | COCs with 35 mcg EE or less | Psychomotor impairment, sleepiness scale, nurse rated sedation scale, memory (recall/recognition) | ALP, LOR, and TRZ produced greater psychomotor performance impairment in the OC users. No difference in sedation or memory. | Not blinded Same study as Stoehr et al., reported number of subjects inverted for OC/control groups Not powered for clinical outcomes |
Fair | |
| Somos 1990 Funding not stated |
Observational | Healthy women on COCs (n=72) who also took a concurrent sedative or hypnotic | Diazepam (5 mg), nitrazepam (5–10 mg), chlordiazepoxide (5 mg), meprobamate (200 mg) taken consistently over 14 days to 2 months | COCs with 50 mcg EE or less and LNG | Breakthrough bleeding (BTB), pregnancy | BTB in 36.1% of women, no pregnancies. Most BTB occurred with chlordiazepoxide (12/19) and meprobamate (11/17). One of 15 women on diazepam and 2/21 on nitrazepam experienced BTB. |
Did not control dose or duration of use of benzodiazepines. No statistics performed. Follow up duration not clear. Baseline bleeding retrospective and descriptive limiting ability to compare outcomes with/without benzo |
Poor | |
| PK studies for oral benzodiazepines | |||||||||
| Abernathy 1983 US Public Health Service |
PK Parallel | Healthy women on COC (n=17) vs not on COCs (n=14) (age 19–37; matched by smoking) | Single dose of 30 mg oral oxazepam (cycle day not specified) | COCs with 50 mcg EE or less | Oxazepam VD, t1/2 clearance, free fraction in plasma over 48 h |
No significant difference in any measures | No report of AUC, tmax, Cmax. OC formulation varied and unspecified. |
Fair | |
| Patwardhan 1983 Veterans Administration and NIH |
PK Parallel | Healthy women on COCs (n=5) vs not taking COCs (n=6) (age 21–33) | Single dose of 45 mg oral oxazepam (cycle day not specified) | Norethindrone 1 mg and EE 50 mcg | Oxazepam Vd, t1/2, clearance over 48 h | OZM-t1/2 ↓NS Clearance ↑ 157% (p<.01) Vd higher (NS) |
No report of AUC, tmax, Cmax Small sample size |
Fair | |
| Stoehr 1984 Upjohn Company |
PK Parallel | Women on COCs (n=19) vs not taking COCs (n=21) (matched by age, weight, smoking status) | Single oral doses of either: triazolam 0.5 mg and temazepam 30 or alprazolam 1 mg and lorazepam 2 mg, dosed 28 days apart | COCs with 35 mcg EE or less | Benzodiaz. Vd, t1/2, AUC, elimination constant, clearance, Cmax, tmax |
No changes except where noted TRZ: no change TMZ: AUC down from 9600 ng/ml*h. control to 5840 ng/ml*h. OCs, p<.05), elimination constant up from 0.052 h−1 control to 0.087 h−1 OCs, p<.005. ALP: AUC control-241 ng/ml*h. COC-326 ng/ml*h. p<.01, elimination constant Control-9.6 h−1 COC-12.4 h−1, p<.005. LOR: elimination constant Control-0.042 h−1 COC-0.054 h−1, p<.025. |
Included AUC, tmax, Cmax Groups matched |
Fair | |
| Scavone 1988 US Department of HHS |
PK Parallel | Healthy women on COCs (n=16) vs not taking COCs (n=23) (matched by age and weight,) | Single dose of 1 mg oral alprazolam (cycle day not specified) | COCs with 50 mcg EE or less | Alprazolam AUC, t1/2, Vd, free fraction, clearance over 48 h | No significant difference in AUC, t1/2, Vd, clearance. Free fraction (% unbound) slightly higher in COC users. | Cmax, tmax not reported | Fair | |
ALP, alprazolam; Cmax, maximum concentration; LOR, lorazepam; t1/2, half life; tmax, time to maximum concentration; TMZ, temazepam; TRZ, triazolam; Vd, volume of distribution.