Evaluation of consumer self-selection of a proposed over-the-counter, progestin-only daily oral contraceptive.

OBJECTIVES: In an effort to switch a norgestrel 0.075 mg progestin-only pill (Opill) from prescription to over-the-counter, we conducted this study to assess whether consumers can use the drug facts label alone to guide appropriate self-selection. STUDY DESIGN: Two studies assessed self-selection: (1) an all-comers, actual-use study evaluating self-selection before purchasing and using norgestrel 0.075 mg and (2) the Targeted Breast Cancer Self-Selection Study evaluating theoretical self-selection among participants with a history of breast cancer. RESULTS: In the actual-use study, based on the label, 1670/1772 participants (94%) were appropriate for use of norgestrel 0.075 mg; 102 (6%) were not appropriate. Of the 102, 66 (65%) correctly did not select and 36 (35%) responded it was okay for them to use norgestrel 0.075 mg. Of the 36 participants who incorrectly self-selected, one had a history of breast cancer and thus might have been adversely affected had they taken norgestrel 0.075 mg. In the Targeted Breast Cancer Self-Selection Study (N = 206), 97% of participants correctly stated norgestrel 0.075 mg was not appropriate for them. CONCLUSIONS: The proposed over-the-counter label enables 98% of potential users to self-select norgestrel 0.075 mg appropriately. Only 2% of potential purchasers may have bought and started to use norgestrel 0.075 mg inappropriately. For two-thirds of these, the potential benefits of their use of the method outweighed any theoretical risks. Adverse clinical consequences of norgestrel 0.075 mg use are unlikely even in those rare cases when the drug facts label was not followed. IMPLICATIONS: The balance of the risk of inappropriate selection to the benefit of taking an over-the-counter progestin-only pill appears to be very much in favor of an overall benefit in terms of unintended pregnancy prevention.

Evaluation of adherence to a daily progestin-only pill in a simulated over-the-counter setting.

OBJECTIVE: The Adherence with Continuous Dose Oral Contraceptive: Evaluation of Self-Selection and Use (ACCESS) study assessed whether consumers can adhere to the regimen for a progestin-only pill (norgestrel 0.075 mg) in an over-the-counter (OTC) setting. STUDY DESIGN: An actual use study in a simulated OTC environment assessed adherence to directions to take norgestrel 0.075 mg every day at the same time in 883 participants for up to 24 weeks. RESULTS: Eighty-five percent (747/883) of participants reported ≥85% adherence to taking norgestrel 0.075 mg every day and reported taking their dose within three hours of their scheduled dosing time on 96% of days. When accounting for use of a condom for 48 hours if a pill was missed, participants reported correctly following the label's directed use for 97% of doses overall, with 95% of participants following label directions for ≥85% of doses. The main limitations were related to finding a balance between intensely collecting data to ensure accurate assessment of adherence and leaving users to behave as they would in a real OTC situation without healthcare practitioner intervention. We observed that some participants reported taking more doses than they could have based on the supply of medication given to them. To fully examine the situation, and the impact on the conclusions, additional post hoc sensitivity analyses were performed, and showed remarkably consistent results. CONCLUSIONS: Consumers were highly adherent to taking norgestrel 0.075 mg when using only the information provided by the proposed OTC label. IMPLICATIONS: Adherence to a daily oral contraceptive pill was high when obtained OTC. This suggests that effectiveness of an OTC pill is likely to be like that of a prescribed pill and easier access to this effective contraceptive should allow more opportunity to prevent pregnancy.

Modeling the potential benefit of an over-the-counter progestin-only pill in preventing unintended pregnancies in the U.S.

OBJECTIVES: To develop a model to estimate the possible impact of use of an over-the-counter (OTC) progestin-only pill (POP) on the number of unintended pregnancies in the United States. STUDY DESIGN: Using typical use failure rates (7% for POPs), we compared the expected number of unintended pregnancies for two theoretical cohorts of 100,000 women: one which purchased and used an OTC POP exclusively for contraception, the other using contraceptive methods at proportions obtained from an actual-use clinical trial simulating OTC use of norgestrel 0.075 mg (including 35% using no method and only 19% using hormonal contraception or long-acting contraceptives). Sensitivity analyses were conducted using alternative model inputs such as different failure rates for OTC POPs and varied alternative contraceptive method mix. RESULTS: An estimated 37,624 unintended pregnancies would occur annually if 100,000 women continued their usual contraceptive method as used at baseline in the actual use trial. This would be reduced by 81% to 7,000 pregnancies with the exclusive use of an OTC POP - a net reduction of 30,624 unintended pregnancies annually. While the number of unintended pregnancies prevented varied as the model parameters were modified (ranging from 1,461 to 34,124), a net benefit of OTC POP use was observed over a wide range of input values. CONCLUSIONS: Using data from a real-world contraception user profile, our model suggests that use of an OTC POP could reduce the overall number of unintended pregnancies in the United States. This conclusion remains true across a wide range of modeled scenarios. IMPLICATIONS: The estimates suggested by this model are supportive of an OTC switch for a POP.

Adherence among a cohort taking progestin-only pills prescribed by a healthcare provider: Results of the BENCHMARK study.

OBJECTIVES: To measure adherence over six months of progestin-only pill (POP) use. STUDY DESIGN: Prospective observational cohort study measuring adherence to daily dosing and timing of dose in patients prescribed a POP, with up to six months of follow-up, conducted from January to October 2020. A pharmacy benefit manager identified potential participants with a newly prescribed POP and extended an invitation to participate. We enrolled qualified respondents by telephone, trained them to use an electronic diary to report daily whether they had taken their POP and at what time. We followed participants for up to six months. We calculated adherence to daily pill taking as the proportion of evaluable days in which a participant took a POP, and the proportion of participants reporting ≥85% adherence. We calculated adherence to same time each day as the proportion of doses taken no later than three hours after the previous dose time of day. RESULTS: The user population comprised 199 participants, 154 (77.4%) of whom completed six months of follow-up. The majority (n = 170, 85.4%) were taking norethindrone. Norethindrone users reported POP intake on 22,327 (96.4%) of 23,156 evaluable days, with 155 (91.2%) participants reporting ≥85% adherence; less than half (n = 73, 42.9%) reported 100% adherence. Participants reported adherence to same time each day on 21,698 of 22,157 (97.9%) evaluable days. CONCLUSIONS: Among participants taking a prescribed POP, participants demonstrated high adherence for daily pill taking and the same time of day, though the majority were not 100% adherent. IMPLICATIONS: This study reports data specific to adherence among those taking a progestin-only pill (POP) in the prescription setting. Clinicians who counsel patients about POP use should be aware that majority of patients were not 100% adherent, although most report ≥85% adherence.

A review of the effectiveness of a progestogen-only pill containing norgestrel 75 µg/day.

OBJECTIVES: To review published data on the effectiveness of a progestogen-only pill containing norgestrel 75 µg/day which should be under consideration by the FDA in 2022 for sale over the counter in the US. STUDY DESIGN: A literature search in MEDLINE, EMBASE, and COCHRANE REVIEWS using specified search terms and adding related cross-references. RESULTS: We identified a total of thirteen relevant studies of women using norgestrel 75 µg/day. None were reported with the rigor characteristic of trial reporting today. Nevertheless, six studies provided data on 3,184 women who were not breastfeeding, followed for over 35,000 months and reported a range of overall failure rates during typical use of norgestrel 75 µg/day from 0 to 2.4/hundred woman-years giving an aggregate Pearl Index of 2.2. Seven additional studies involved 5,445 women some of whom were breastfeeding for at least part of the period of follow-up. More than 36,000 months of use yielded 12-month life table cumulative pregnancy rates for norgestrel 75 µg/day ranging from 0 to 3.4. We were unable to calculate an aggregate Pearl Index for the breastfeeding studies because of lack of crucial data. CONCLUSIONS: The data support that norgestrel 75 µg/day is highly effective in clinical use, with similar estimates of failure in breastfeeding and non-breastfeeding women, providing support to the case for approval without the need to see a healthcare provider.

Pharmacokinetic profile of extended-release versus immediate-release oral naproxen sodium after single and multiple dosing under fed and fasting conditions: two randomized, open-label trials.

PURPOSE: Extended-release (ER) naproxen sodium provides pain relief for up to 24 hours with a single dose (660 mg/day). Its pharmacokinetic profile after single and multiple dosing was compared to immediate release (IR) naproxen sodium in two randomized, open-label, crossover studies, under fasting and fed conditions. METHODS: Eligible healthy subjects were randomized to ER naproxen sodium 660-mg tablet once daily or IR naproxen sodium 220-mg tablet twice daily (440 mg initially, followed by 220 mg 12 hours later). Primary variables: pharmacokinetic parameters after singleday administration (day 1) and at steady state after multiple-day administration (day 6). RESULTS: Total exposure was comparable for both treatments under fasting and fed conditions. After fasting: peak naproxen concentrations were slightly lower with ER naproxen sodium than with IR naproxen sodium but were reached at a similar time. Fed conditions: mean peak concentrations were comparable but reached after a longer time with ER vs. IR naproxen sodium. ER naproxen sodium was well tolerated, with a similar safety profile to IR naproxen sodium. CONCLUSIONS: The total exposure of ER naproxen sodium (660 mg) is comparable to IR naproxen sodium (220 mg) when administered at the maximum over the counter (OTC) dose of 660-mg daily dose on a single day and over multiple days. The rate of absorption is delayed under fed conditions.

Efficacy of single-dose, extended-release naproxen sodium 660 mg in postsurgical dental pain: two double-blind, randomized, placebo-controlled trials.

OBJECTIVE: To evaluate the efficacy of a novel formulation of extended-release/immediate-release (ER) naproxen sodium over 24 h in a dental pain model. RESEARCH DESIGN AND METHODS: Two randomized, double-blind, placebo-controlled trials in moderate to severe pain after extraction of one or two impacted third molars (at least one partial mandibular bony impaction). Treatment comprised oral ER naproxen sodium 660 mg (single dose), placebo (both studies) or immediate-release (IR) naproxen sodium 220 mg tid (study 2). MAIN OUTCOME MEASURES: Primary efficacy endpoint: 24-h summed pain intensity difference (SPID). Secondary variables included total pain relief (TOTPAR), use of rescue medication. All treatment-emergent adverse events were recorded. CLINICAL TRIAL REGISTRATION: NCT00720057 (study 1), NCT01389284 (study 2). RESULTS: Primary efficacy analyses: pain intensity was significantly lower over 24 h with ER naproxen sodium vs. placebo (p < 0.001), with significant relief from 15 min (study 2). In study 2, ER naproxen sodium was non-inferior to IR naproxen sodium, reducing pain intensity to a comparable extent over 24 h. TOTPAR was significantly greater with ER and IR naproxen sodium vs. placebo at all time points, with generally comparable differences between active treatments. Significantly more placebo patients required rescue medication vs. ER and IR naproxen sodium from 2-24 h post-dose. Once daily ER naproxen sodium was generally safe and well tolerated, with a similar safety profile to IR naproxen sodium tid. LIMITATIONS: The studies were single dose, with limited ability to assess efficacy or safety of multiple doses over time. As the imputed pain score meant that estimated treatment differences may have been biased in favor of ER naproxen sodium, a post hoc analysis evaluated the robustness of the results for pain relief. CONCLUSIONS: A single dose of ER naproxen sodium 660 mg significantly reduced moderate to severe dental pain vs. placebo and was comparable to IR naproxen sodium 220 mg tid. Significant pain relief was experienced from 15 min and sustained over 24 h, resulting in a reduced need for rescue medication. ER naproxen sodium 660 mg once daily is a convenient and effective therapy providing 24 h relief of pain.

Gastrointestinal adverse effects of short-term aspirin use: a meta-analysis of published randomized controlled trials.

BACKGROUND AND OBJECTIVES: Aspirin is widely used for short-term treatment of pain, fever or colds, but there are only limited data regarding the safety of this use. To summarize the available data on this topic, we conducted a meta-analysis of the published clinical trial literature regarding the gastrointestinal adverse effects of short-term use of aspirin in comparison with placebo and other medications commonly used for the same purpose. DATA SOURCES AND METHODS: An extensive literature search identified 119,310 articles regarding possible adverse effects of aspirin, among which 23,131 appeared to possibly include relevant data. An automated text-mining procedure was used to score the references for potential relevance for the meta-analysis. The 3,983 highest-scoring articles were reviewed individually to identify those with data that could be included in this analysis. Ultimately, 78 relevant articles were identified that contained gastrointestinal adverse event data from clinical trials of aspirin versus placebo or an active comparator. Odds ratios (ORs) computed using a Mantel-Haenszel estimator were used to summarize the comparative effects on dyspepsia, nausea/vomiting, and abdominal pain, considered separately and also aggregated as 'minor gastrointestinal events'. Gastrointestinal bleeds, ulcers, and perforations were also investigated. RESULTS: Data were obtained regarding 19,829 subjects (34 % treated with aspirin, 17 % placebo, and 49 % an active comparator). About half of the aspirin subjects took a single dose. Aspirin was associated with a higher risk of minor gastrointestinal events than placebo or active comparators: the summary ORs were 1.46 (95 % confidence interval [CI] 1.15-1.86) and 1.81 (95 % CI 1.61-2.04), respectively. Ulcers, perforation, and serious bleeding were not seen after use of aspirin or any of the other interventions. CONCLUSIONS: During short-term use, aspirin is associated with a higher frequency of gastrointestinal complaints than other medications commonly used for treatment of pain, colds, and fever. Serious adverse events were not observed with aspirin or any of the comparators.