A Primary Care Perspective on Prescribing for Women

Medicines For Women

14. A Primary Care Perspective on Prescribing for Women

Dee Mangin^{1, 2}

(1)

Department of Family Medicine, McMaster University, Hamilton, ON, Canada

(2)

University of Otago, Christchurch, Dunedin, New Zealand

Dee Mangin

Email: mangind@mcmaster.ca

Introduction

While evidence for the prescribing of medicines is largely generated in secondary care settings, the majority of prescribing actually occurs in the primary care setting. This raises uncertainties about generalizability of data on efficacy and safety for a population where a greater proportion have milder forms of illness. Prescribing for women in primary care is especially challenging for two reasons: firstly because of the uncertainties inherent in the evidence for safety and efficacy of prescription medicines in women, and secondly due to the complexity of the primary care patient context.

Generation of evidence for prescribing in secondary care settings, likely overstates the magnitude of any efficacy in the primary care population where the milder end of the spectrum of disease is more commonly seen than in clinical trials (Kendrick et al. 2008). Evidence for prescribing medicines for women in primary care is even less certain than for men. Women are less likely to have been included in research on medicines. Chapter 17 documents how recent this issue is – it wasn’t until 1993 that the NIH Revitalisation Act mandated the inclusion of women in clinical research protocols –yet evidence is emerging that women may respond differently than men, as outlined in this chapter. In some cases, women are less likely to benefit and overall are more likely to suffer adverse effects of medicines than men.

Women are prescribed more medicines than men – on average 5 compared with 3.7 for men in a United States study (Medco Health Solutions & Society for Women’s Health Research 2012). Data from primary care in the United States and Scandinavia also shows some drug groups are prescribed more often to women than to men – in particular psychotropic medication and pain medications (Hausken et al. 2007). Women are also likely to suffer more multiple comorbidities than men, and, as managing multiple comorbidities now represents the majority of primary care work, women are vulnerable to the inherent risks of being prescribed multiple medications simultaneously in this situation, compounding their increased vulnerability to adverse effects and dose inaccuracies.

Further, there are reproductive issues to take into consideration. Prescribing in primary care is longitudinal – over a woman’s lifetime, and that of her family. Because of the possibility of transmission of most drugs across the placenta, women and primary care providers have to factor the future possibility of pregnancy in to their decisions to take and prescribe medicines. Prescribing of some specific drugs and devices for women that are commonly used in primary care (contraception, hormone replacement therapy, bisphosphonates) have been covered in previous chapters so will not be repeated. Rather, this chapter deals with broad principles and issues for prescribing in primary care, attending to some other common patterns and problems of prescribing for women in this setting. It covers both the background for prescribing for women in these circumstances and includes practical recommendations for dealing with the uncertainties.

Assessing Risk and Benefit in Women

Assessing the value of medicines in women requires balancing the evidence for effectiveness and safety along with a woman’s preferences and priorities for care. As already noted, assessment of the evidence to support primary care prescribing for women is more complex than for men. Some research indicates that women may experience the benefits and risks of some medicines differently to men. However, such evidence to nuance prescribing is limited as most regulators including the FDA do not require analysis of sex differences in either efficacy or safety outcomes when licensing medicines. In fact, until relatively recently, the FDA had a ban on women being included in early stage clinical trials (Cotton 1993). Active efforts have been made to increase recruitment of women into clinical trials and disaggregate reporting by gender. This included the 1993 NIH Act which mandated participation, and guidelines from Health Canada in 1994 advocating for inclusion of women at all stages of research into drug development. However, a study published 20 years later indicates there is little change in published research (Geller et al. 2011).

Some examples of these differences in women’s experiences of the benefits and risks of medicines include statin drugs, which are very commonly prescribed in primary care. An analysis across all major prevention trials showed the absolute risk of benefit was less for women than for men, with no demonstrated statistically significant advantage in all-cause mortality, no clinically significant benefit in primary prevention and less absolute benefit (and therefore a higher number needed to treat) than men in secondary prevention (Roberts and Redberg 2013). Women also experienced some side effects such as myopathy and diabetes development at a greater rate than men (Roberts and Redberg 2013). Diuretics are more likely to be chosen for treatment of hypertension in women than in men (Klungel et al. 1997, 1998) however research indicates women are more susceptible to hyponatremia as a result, and this can be after treatment is well established (Sharabi et al. 2002). In some cases, drugs work less effectively; women are less responsive to anesthesia, for instance, than men are (Buchanan et al. 2011).

Acknowledging the uncertainties in the data for women on risks and benefits of medicines is an important part of the shared decision making process around decisions to take medicines. Women’s preferences and priorities for care are equally important, and a key aspect of Evidence Based Medicine, which incorporates, in equal measure, research evidence, the patient’s context and patients’ preferences for care. These aspects are synthesized with clinical wisdom in the shared decision making process (Sackett et al. 1996).

Women and Adverse Reactions to Medicines

Women experience higher rates of adverse drug reactions than men, even when age and rate of exposure are taken into account (Figueras et al. 1994; Tran et al. 1998; Domecq et al. 1980; Pouyanne et al. 2000; Fattinger et al. 2000; Rademaker 2001; Martin et al. 1998; van der Klauw et al. 1998). For example, one study based in the UK that analysed ADR patterns by age and sex found nearly double the ADR rate per unit of exposure for women compared to men (20.6 per 10,000 patient months exposure compared with 12.9 for men. OR 1.5 (1.5–1.7)) (Martin et al. 1998).

While it is possible there are other reporting biases, there are pharmacokinetic differences between women and men as well as known differences in metabolism, both increased and decreased, related to specific drugs (Kando et al. 1995; Harris et al. 1995; Ochs et al. 1981).

Women are at greater risk of some particular drug side effects. A review conducted by the US General Accounting Office of 10 prescription drugs withdrawn from the market (January 1997 to December 2000) indicated that eight of these posed greater health risks for women than men (troglitazone, lotronex, fenfluramine, dexfenfluramine, mibefradil, terfenadine, cisapride, astemizole). The first four drugs were prescribed more often to women, which may have accounted for the increased reports of harms with these four, however, in the second group of four, where there was no differential, the likely reason was felt to be women’s increased susceptibility to the adverse cardiovascular effects of the drugs. Mibefradil lowered or stopped the heart rate in healthy adults and in particular in elderly women. Cisapride, astemizole and terfenadine are all known to prolong the QT interval. (Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women, United States General Accounting Office Washington, DC, GAO 01286R) Six of these eight drugs caused heart problems in women (Heinrich 2001).

QT prolongation is one example, and is an important one as it can represent the additive effect of several medicines. Research has documented the greater sensitivity of women to the effects of medicines that affect the heart and prolong the QT interval, the influence of their menstrual cycle and the corresponding increase in life-threatening arrhythmias and deaths in women (Benton et al. 2000; Yap and Camm 2003; Ebert et al. 1998; Bednar et al. 2002).

Whenever data have been available for analysis, more women are reported to have developed heart arrhythmias with cardiovascular medicines despite the greater rate of prescription of anti-arrhythmic agents to men (Makkar et al. 1993). At least 90 prescription medicines have this effect on the heart and many may be co-prescribed in multimorbidity. Research indicates that when drug interaction warnings for QT interval based interactions are overridden, ECGs are only ordered by prescribers 33 % of the time and in those where ECGs are ordered, 31 % had clinical significant QTc interval prolongation (Van Der Sijs et al. 2009).

Additionally some particular risks pertain almost exclusively to women, either because the drugs are mostly prescribed to women or because the side effect is mostly experienced by women. For example, a recent paper reported a risk of atrial fibrillation with long term bisphosphonates (Sharma et al. 2013) which are prescribed to high numbers of women worldwide for osteoporosis (see Chap. 12), and suggestions of an increased risk of breast cancer with calcium channel blockers (Coogan 2013). While many of these prescriptions will be initiated by secondary care prescribers, primary care prescribers are best placed to assess potential cumulative adverse effects of drugs initiated by multiple prescribers – for example, the effects of additive QT prolongation or pro-haemorrhagic risk. There are multiple medications available that are commonly prescribed that increase the tendency to haemorrhage – from the obvious such as warfarin, aspirin, antiplatelet agents, to the less obvious which may be additive in their effect and, given the frequency of prescription, are likely to be co-prescribed e.g. SSRIs, cholesterol lowering agents, NSAIDs.

The Super Precautionary Principle

Women have hormonal cycles, smaller organs, generally smaller body mass index and higher body fat composition, all of which are thought to play a role in how drugs affect women’s bodies (see Chap. 2for more detail). There may also be basic differences in gene expression, which can make differences in the way we metabolize drugs. For example, men metabolize caffeine more quickly, while women metabolize certain antibiotics such as erythromycin and anxiety medications such as diazepam more quickly.

The entire prescribed medicine research pipeline is male dominated – from animal studies that are done in male animals to avoid any hormonal effects, to clinical trials, which have been also largely performed on men, yet the efficacy and safety results, datasheets and recommended doses take a ‘one size fits all’ approach. The need for being alert to the potential for these differences between men and women is rarely accounted for in either research language or in primary care datasheets and guidelines recommending dosing.

The one drug where differential recommendations are made is zolpidem, a commonly prescribed sleeping tablet in the United States, where it was discovered that the same dose resulted in a doubling of blood levels in women compared with men (FDA 2013). In 1992 these data were included in the FDA review of the drug, however the recommendation for differential dosing was not made until January 2013 (News).

To account for the differences discussed here, I would advise use of a ‘super precautionary principle’. This might mean, in prescribing medications for chronic conditions in women in primary care, that dosing could start at the lowest possible dose of a medication – lower than the standard dose recommendation – and be titrated upwards according to effect where possible.

The Complex Prescribing Landscape of Primary Care

Prescribing in primary care is more complex than in secondary care. Family physicians address a mean of 3.05 problems per visit and in 37 % of the encounters more than three problems are addressed (Katerndahl et al. 2011). The more comorbidities a patient has, the more drugs they are prescribed. The more drugs they are prescribed, the higher the risk of adverse events.

In an aging population, the majority of patients attending primary care now experience multiple chronic comorbidities (Mangin et al. 2012). Half of people over 65 years of age have at least three coexisting chronic conditions. One in five has five or more. Although the proportion of patients who have comorbidities increases in older age groups, the largest numbers of patients with multiple comorbidities are under 65 years of age and more than half of patients attending primary care in the UK have multiple chronic conditions and such patients take up an even greater proportion of consultations (Salisbury et al. 2011). In a US study of Medicare beneficiaries, the proportion of patients with more than five treated conditions increased from 31 % to 50 % from 1987 to 2002 (Thorpe and Howard (2006). Women live longer than men and are also more likely to suffer from chronic disease (Malmusi et al. 2012). In some conditions, for example heart disease, they experience these at an older age (Roberts and Redberg 2013). Age-related changes in hepatic and renal function lead to alterations in drug clearance, and this, combined with the uncertainties in the evidence overall and for women in particular, makes prescribing in this situation complex.

Seniors in developed countries take a median number of seven medications (Mangin et al. 2012; McCarthy et al. 2007). Drugs for cardiovascular risk such as high blood pressure and cholesterol are the most commonly prescribed in seniors over 65 as well as drugs for heart failure. In Canada, spending in public drug programs was greatest on statins for cholesterol lowering, proton pump inhibitors for dyspepsia, gastro-oesophageal reflux and ulcer treatment, and calcium channel blockers use for hypertension and other cardiovascular conditions. The highest growing expenditure group is TNF alpha inhibitors used for conditions such as rheumatoid arthritis and Crohns disease (Canadian Institute for Health Information). In the United States in adults over 60 cholesterol drugs are the most commonly used (45 % of the population) followed by beta blockers and diuretics (Gu et al. 2010). Medication side effects and polypharmacy, and associated morbidity and mortality from drug side effects are major and costly problems for healthcare and for individual women. In a Canadian study people taking more than five medications were more likely to experience a medication related side effect that required health care than those taking less than 2 (13 % vs. 6 %) (CIHI 2011). Less than half of those taking more than five medications reported having a medication review (CIHI 2011).

Margaret (Case Study Box 14.1) is a very typical woman of her age – with two conditions that cause symptoms and three risk factors for conditions that may cause symptoms in the future. Margaret’s doctors follow the condition based guidelines for each of her problems. An elegant study by Boyd et al. demonstrates that this results in 19 doses of 12 different medications (thiazide diuretic, ACE inhibitor, metformin, sulphonlyurea, statin, B2 agonist inhaler, aspirin, calcium, Vitamin D, alendronate, NSAIDs, a proton pump inhibitor) taken at five times during the day (Boyd et al. 2005). Merging data on interactions and recent data on emerging adverse events updates Boyd’s estimate of potential interactions either between drugs or drugs and diseases to 16. These are outlined in Table 14.1

Table 14.1

Potential drug-drug and drug-disease interactions in case study “Margaret”

Drug	Interacting drug/condition	Interaction risk
Statin	Diabetes	Increased risk of diabetes
ACE inhibitor	Diuretic, aspirin	Increased risk renal failure
NSAID	Hypertension	Increased risk renal failure
NSAID	Hypertension	Increased risk hypertension
NSAID	Aspirin	Bleeding
Calcium	Hypertension, diabetes	Increased risk CV events
PPI	COPD	Increased risk pneumonia
Thiazide	Diabetes	Increased risk diabetes
Aspirin	Alendronate	GI upset
Calcium	Aspirin	Decreased efficacy
Thiazide	Sulphonylurea	Decreased efficacy
Calcium	Alendronate	Lowered serum level alendronate
NSAID	Diuretic	Decreased efficacy
Sulphonylurea	Aspirin	Hypoglycaemia
Aspirin	ACE inhibitor	Decreased efficacy
Alendronate	Hypertension	Both increase the risk of atrial fibrillation

Applying single disease guidelines in multimorbidity to a woman (like Margaret) with five chronic comorbidities, no matter what they are, results in potentially harmful polypharmacy (Boyd et al. 2005). Measurably better care may be meaningfully worse for the patient. This is a more common situation among women and discriminatory and wise prescribing is required, prioritising medicines that are most important to the patient and being alert to side effects and interactions. While the initiation of some of these medicines might be in secondary care settings, it is the primary care clinician who is almost always responsible for ongoing prescriptions. With increasing specialisation and subspecialisation, and guidelines to match this, prescribing is increasingly done with a partial focus on the patient – on one system or disease of expertise.

Similarly, evidence of drug efficacy and safety is also generated largely in single disease, controlled trial settings – patients who are older or who have multiple comorbidities or other medications are frequently excluded from clinical trials of medicines. In contrast, the expertise of primary care clinicians is a view that encompasses the whole patient – their multiple comorbidities and medications – with a focus on the individual: patient centered care is a core value of primary care. Primary care prescribers are also experts in longitudinal care, making them best placed to assess the relative value of different medications over time. This is crucially informed by the direct observation of the actual effects and side effects of medicines over time in the individual sitting in front of them. It is often forgotten that the ‘n = 1 trial’ is the highest level of evidence.

Box 14.1: Case Study: Margaret

Margaret is 70 years old and has Chronic Obstructive Pulmonary Disease, arthritis, diabetes, hypertension and osteoporosis. Her arthritis stops her from playing with her grandchildren as she would like to, while her COPD makes her too breathless to go dancing with her husband any more. The other conditions she is only aware of because her primary care doctor did some measurements.

Management of Polypharmacy

Despite the evidence of preventable morbidity and mortality from adverse drug reactions (Baker et al. 2004; Field et al. 2005), in Canada for example, the majority of patients with multimorbidity who are taking multiple medications have never had a formal drug review (CIHI 2011). Trials of stopping medicines indicate that stopping or reducing doses of diuretics, anti-hypertensives, antipsychotics and proton pump inhibitors can be successful and their effectiveness is often increased by tapering (Iyer et al. 2008; Nelson et al. 2002; Campbell et al. 1999). Trials of multiple medication discontinuation also indicate that this can be done successfully and without adverse consequences for the patient (Garfinkel and Mangin 2010; Garfinkel et al. 2007).

A pragmatic prioritisation framework on which to base discussion with a woman with several comorbidities and on multiple medications has been suggested as covering (Holmes et al. 2006):

Assessment of individual potential to benefit is important (if the medication has to be taken for 5 years to realise benefit and the patient is unlikely to live 5 years then benefit will not be realised) and this must be judged against the risks. For example, pravastatin must be taken for prevention of stroke in those at high risk for 5 years to realise 1.4 % absolute risk difference in stroke. If a woman is likely to die in the next year or two then the potential for benefit will be markedly reduced and must be measured against the risks which ensue from the outset of taking the medication.

In avoiding the harms of polypharmacy a rule of thumb is to aim for five medications. Beyond this, the risk of increasing morbidity with side effects rises substantially (Steinman et al. 2011; Buck et al. 2009). There are a variety of tools available to support medication prioritisation and suggest drugs to avoid if possible in older age, such as the Beers list, STOPP and START criteria, the Medication Appropriateness Index (Hanlon et al. 1992), the Drug Burden Index (Hilmer et al. 2007), as well as process guides to considering priorities (Ostini et al. 2011; BPAC 2010; Gallagher and O’Mahony 2008; Scott et al. 2012; Alexander et al. 2006; Mangin and Kerse 2010; Garfinkel and Mangin 2010; Cross 2013).

‘Legacy Drugs’

There are a group of ‘legacy drugs’ (drugs that efficacy data suggest should have a time limited prescription duration, but are often carried on indefinitely) the prescription of which is only indicated for 1–5 years with no evidence of additional benefit beyond this period to offset against the ongoing potential harms. These drugs can add to the polypharmacy burden unnecessarily. Drugs such as antidepressants, osteoporosis drugs, statins and proton pump inhibitors are examples of legacy drugs, and as previously detailed, many of these are prescribed much more frequently to women. Hormone Replacement Therapy (HRT) is another important example of a medication that should have a planned stop date. A detailed review of HRT – more correctly known as Menopause Hormone Treatment (MHT) – and the evidence and recommendations for use is included in Chap. 11. Prescription of drugs such as antibiotics is self-limiting, as usually only a single prescription is given, however the groups of legacy drugs require repeat prescribing, usually in primary care, and most systems in primary care do not provide a stop date alert. It is likely that multiple prescribers contribute to this legacy effect, and primary care clinicians are best placed to assess and address this issue.

A good prescriber is one who regularly pays attention to stopping and reducing the dose of medicines. Almost all drugs are eligible for a trial of discontinuation and equally importantly, it should not be regarded as a failure to have to restart a paused medication after such a trial. Regular recall to review the medications of women with multiple comorbidities should be a scheduled part of primary care. To prescribe well: adjust, watch, listen and adjust again.

New Is Not Necessarily Better: The Implications of Marketing Drugs to Women in Primary Care

The United States and New Zealand are the only countries allowing direct to consumer advertising. Many other countries have ‘disease-oriented ads’ and advertorials disguised as articles in women magazines with checklists for diagnosing disease, that are generated from the PR campaigns of pharmaceutical companies. Women are targeted more in advertising of new drugs. Women’s magazines and daytime television are the most common places for presentation of drug advertising (Brownfield et al. 2004; Bell et al. 2000). Advertising targeting women is problematic for a number of reasons: it medicalises normal human experience, contains stereotyped portrayals of women, provides unrealistic expectations of effectiveness and minimises safety concerns (Mintzes 2010).

In one study of advertising in medical journals, 57 % of the advertisements for psychoactive drugs featured women and older women were targeted more (67 % of those directed at age 20–40 were for women, as were 90 % of the advertisements directed at women over 80) (Munce et al. 2004). Physicians are responsive to patients requests for advertised medicines – a study using actors as ‘female standardized patients’ trained to present with either depression or emotional responses to a stressful life situation, and asking or not asking for an antidepressant advertised on television, found that a woman’s request for an antidepressant predicted whether she was likely to leave the office with a prescription much more than whether she had a condition an antidepressants drug would be useful in treating (Kravitz et al. 2005). In a New Zealand survey 18 % of the population had asked for a medicine advertised on television and over half of these patients had received it, and 29 % of women had used a magazine or newspaper as a source of health information compared to 15 % of men (Toop et al. 2003b). Advertisements such as those for sibutramine (Reductil^©) and the oral contraceptive pill Diane 35^©, specifically targeted at women, have had to be withdrawn for inaccuracy of claims (Toop et al. 2003a; Mintzes 2004).

Rarely do new medicines offer substantial benefit. The French Independent Drug Bulletin La Revue Prescrire evaluates all new drugs coming onto the market using systematic review of all available evidence from clinical trials and using both published and unpublished data. Over a 5 year period they evaluated nearly 1,000 medicines and found only 2 % as clear treatment advances and 9 % as having some advantages (Mintzes and Mangin 2009). Less is known about the safety in the general population of drugs new to the market. Furthermore, clinical trial populations include less women, less people with comorbidities or concurrent medications and less primary care participants (whose illness encompass the less sever end of the spectrum) than ‘real life’ populations of patients. One group have recommended a safe approach is refraining from prescribing a new medicine until 7 years after introduction (Wolfe 2012). It takes even more time for differential and preferential adverse effects in women to filter through after introduction to market.

New drugs to the market are very visible: they are the drugs you are most likely to see in primary care medical journals, and presented by drug representatives and at commercially sponsored continuing medical education events and conferences for primary care clinicians. They are the most likely to come with free gifts and ‘free’ samples for patients attached.

I suggest the following principles: Have a higher threshold for prescribing drugs new to the market to women. Be cautious with dosing if a decision to prescribe is made. The information about efficacy, dose and side effects in women is likely to be less certain than the data provided.

Mind that Drug: Psychoactive Drug Prescription and Women

There are reasons for higher rates of stress in women. Women are more likely to suffer from poverty and economic deprivation, stressful role changes and a higher proportion of women work in stressful jobs. There is also evidence that if a woman and a man go into a primary care office with the same condition, the woman is more likely to emerge with a prescription for a psychotropic agent (Hausken et al. 2007). In addition, the changing stages of reproduction make a woman more likely to have contact with the medical system (for example, consultations for menstrual issues, screening for cervical and breast cancer, pregnancy-related appointments, attending with babies and children and also menopause) and therefore more likely to receive a prescription.

Twice as many psychotropic drugs (drugs that affect the mind) are prescribed for women as for men, and this holds true for the selective serotonin reuptake inhibitor (SSRI) antidepressants, the most common antidepressant class prescribed (Ashton 1991). Women are 70 % more likely to be recorded as experiencing depression in their lifetime than men (Kessler et al. 2003). As well as increased psychological stress, the promotion of screening also contributes to these high rates of prescription, despite evidence that screening for depression is of no benefit (Gilbody et al. 2005). Depression screening tests such as the Edinburgh Postnatal Depression Scale (EPDS) are promoted to assess women during the postpartum period. The range of false positives from this test ranges from 30 % to 70 %. It is designed to pick up minor depression that would benefit from time and support but Oates suggests a lack of counselling resources and skills results in many women with postnatal depression receiving antidepressants rather than non-drug assistance (Oates 2003). There is no evidence for benefit from screening for depression in primary care yet it is widely promoted by commercial interests.

A review of spontaneous adverse drug reaction (ADR) reporting in the US found that during a 10-year period the SSRI fluoxetine was associated with more hospitalizations, deaths or other serious adverse effects reported to the FDA than any other drug in America (Spigset 1999). The most common problems reported with SSRIs are neurological (22 % of ADRs), psychiatric (19.5 %), gastrointestinal (18 %) and dermatological (11.4 %) and women experienced a higher rate of the most harmful of these effects in comparison with men (Spigset 1999).

The rate of SSRI antidepressant prescribing is growing steadily in women and the proportion of women taking an SSRI in most developed countries is now over 10 % and much higher in subgroups in some countries – 30 % of women over 65 in Iceland in 2008 were taking an antidepressant (Pratt et al. 2011; OECD 2013). The evidence shows limited efficacy in the overall primary care population even in short 12 week trials (Arroll et al. 2005). In this meta-analysis by Arroll et al. the absolute difference in response between the antidepressant medication and placebo was 13.5 %, there being 44.5 % remission with placebo versus 58 % with antidepressants at 12 weeks, so nine patients need to be treated for one to benefit (Arroll et al. 2005).

There is also evidence that some of the rise in antidepressant use is driven by patients going on antidepressants and staying on them (Moore et al. 2009; PHARMAC). As discussed in the ‘legacy drugs’ section above, this is likely a combination of failure to review after the maximum 12 months of prescribing for a single episode (Kennedy et al. 2009; NCCMH 2010), reinforced by withdrawal symptoms misinterpreted as recurrence by the patient. Legacy drugs such as SSRIs which have time limited value, should have dates set for active discontinuation when prescribing is first initiated and these should be discussed with the patient.

Mortality and Morbidity from Prescribed Medicine Overdose

Although men still fall victim to prescription drug overdose more often than women, the number of women losing their lives from overdose of prescription drugs rose 400 % between 1999 and 2010 (compared to 250 % for men), according to recent US data from the Centers for Disease Control and Prevention (CDC). Eighteen women die per day of a prescription drug overdose in the U.S. – five times more than 10 years ago. Prescription painkillers have been a major contributor to increases in drug overdose deaths among women. In the United States alone, more than 6,600 women died from a prescription painkiller overdose in 2010 and this accounts for nearly half of all drug overdoses among women. This is four times as many deaths in women than from heroin and cocaine use combined. In 2010, there were more than 200,000 emergency department visits for opioid misuse or abuse among women in the United States; about one every 3 min (CDC 2013).

Prescription Drug Abuse and Women

Forty years ago, pain was widely under-treated with prescription painkillers reserved primarily for cancer pain. Now the scales have tipped the other way and, in some scenarios, pain is being over-treated with addictive medications even when non-addictive approaches would be effective. There are cycles of overprescribing of drugs with addictive potential in women – in previous decades diazepam and other benzodiazepines were over-prescribed to women for stresses that were environmentally generated – labelled in the popular press ‘suburban neurosis’.

Women are more likely to suffer from chronic pain than men and prescription painkillers are now commonly prescribed among women (Nicholas et al. 2011). Women are more likely to be prescribed painkillers as men for the same level of pain (Simoni-Wastila 2000; Chilet-Rosell et al. 2013), against the background that women are 50 % more likely than men to leave their doctor’s office with a prescription, even if they have the same condition (Currie 2003). A UK study found that women who have been abused by their partners have almost double the primary care consultation rate, together with a sevenfold prescription rate of pain medication in the youngest and middle age categories and threefold in the oldest age group (Wong et al. 2007). As discussed above, data from the CDC indicate that women aged 45–54 years have had the most dramatic increases in drug overdose deaths in the United States. Women are also more often prescribed painkillers and for longer periods of time than men.

Health care providers and women can take steps to protect against prescription painkiller overdoses among women by using non-narcotic alternatives for non-cancer pain as well as non-pharmacological modalities. There are some excellent resources freely available as illustrated in Box 14.2:

Reproductive Age Prescribing

The examples of diethylstilboestrol, thalidomide and sodium valproate demonstrate that any medication has the potential for unintended and unknown harm when used in the reproductive age group if pregnancy should occur and important and often rapid informed decisions have to be made about medications by a woman when she becomes pregnant. However the even greater responsibility for the primary care prescriber occurs when prescribing in the reproductive age group, before pregnancy occurs. This responsibility covers three main areas: ensuring timely stop dates for legacy drugs to reduce overall drug exposure, warning re the need for pre-pregnancy discussion and duration of any likely tapering required for any women taking long term medication, and ensuring adequate and effective contraception for any woman taking known teratogens or where data is uncertain (this represents a large group of medicines). Informed discussions should include both what is known but also important unknowns. This is an example of the ‘absence of evidence is not evidence of absence’ principle – for example absence of, or unclear evidence on, effects of drugs taken during pregnancy on subsequent child development should be addressed as an important unknown rather than as reassuring that there is no effect.

Case Study

Carey’s story (Box 14.3) illustrates not just the slippage that occurs in prescribing with ‘legacy drugs’ that are only indicated for limited time periods but also issues around providing the opportunity for informed decision making in the reproductive age group Antidepressants are a good example of a legacy drug mentioned above and are common in younger age groups of women, proton pump inhibitors are another. In the reproductive age group polypharmacy is less of an issue but reducing unnecessary medicine use and reducing the risk of accidental exposure in the first trimester are important aspects of prescribing.

Multiple prescribers, and often withdrawal effects experienced by the patient (as described by Carey in Box 14.3, these are more likely to explain how she felt off the medicine, rather than the return of the indication for which the drugs were prescribed) combine to facilitate ongoing prescribing well beyond the duration of benefit. This has particular implications for women, as it widens the window for exposure during pregnancy. Around a third of pregnancies are unplanned and there are data indicating planning of pregnancy predicts later cognitive and behavioural outcomes in children, independent of a variety of cofactors. This is likely to represent unwitting environmental and drug exposures.

A simple and regularly repeated pregnancy warning to the patient on long term medicines is important but will not suffice. When prescribing such medicines in primary care, explicit attention must be paid to effective contraception and instruction about its use (see section “Reproductive Age Prescribing”) as well as warning when medications will need a significant taper period. A woman who presents for discussion of medication and pregnancy after she is pregnant has already had opportunity for informed shared decision making reduced.

Pertinent to Carey’s case is that fact that, while some studies indicate higher recurrence rates in women with more severe, frequently recurrent (4 or more) episodes of depression (Cohen et al. 2006), the most recent studies indicate that in the kind of population normally treated in primary care there was no higher recurrence rate of depression among well women taking long term antidepressants in those who stop in pregnancy compared with those who continue (Yonkers et al. 2011). However it is not as simple as just stopping as soon as possible. Some drugs such as SSRIs need tapering, so given the lag time between conception, awareness of missed period, testing and primary care visit, as in Carey’s case, it is likely that, by the time she has finished the taper period, the first trimester would be complete. Her capacity to make an informed choice about taking medication in pregnancy is reduced.

Box 14.2: Non Pharmacologic Resources for Managing Non-cancer Pain

“Pain: Understanding what to do about it in less than five minutes” http://www.youtube.com/watch?v=4b8oB757DKc.

“Low Back Pain – Mike Evans Video”

http://www.youtube.com/watch?v=BOjTegn9RuY

“Be the Doctor not the Dealer” https://www.youtube.com/watch?v=QMIHTliEuNk

Box 14.3: Case Study: Carey

Carey is 26 and comes to see you as she did a pregnancy test at home the previous week that is positive. Her last menstrual period was 8 weeks ago – she did the pregnancy test when her period was 10 days overdue and this was 7 days ago. You look in her notes and see she is taking an SSRI. Looking back further you see she has been on this for some years, and had repeat prescriptions written by three of the doctors in the practice. You talk to her and she says she was started on it after the death of her father. It was her first episode of low mood. She says she kept on taking it as she thought it kept her well. “I know I need it still as I forgot it once when I went away for the weekend and I felt terrible, really awful…”

Enabling Informed Choice for Women in the Reproductive Age Group

General practitioners have an important role to play in helping prevent inadvertent fetal exposure to medicines. 11.7 million women of childbearing age are prescribed FDA Category D or Category X medications each year (Schwarz et al. 2005; Andrade et al. 2006). A systematic review of studies in other countries found the proportion of women who were prescribed a drug with positive evidence of fetal risk varies: Denmark (18.7 % of 15,756 women), the Netherlands (21.0 % of 7,500 women) and Canada (6.3 % of 109 344 women) (Daw et al. 2011). In the United States, approximately 6 % of US pregnancies occur in women taking medications with known teratogenic risk (Schwarz et al. 2005; Andrade et al. 2006). The most frequently prescribed Category D and X medications in the primary care setting are anxiolytics, anticonvulsants, antibiotics and statins. Prescriptions for these medications occurred at 1 in 13 visits for women aged 14–44 years (Schwarz et al. 2005). Contraceptive counseling was documented during less than 20 % of these visits and occurred at equally low rates whether category A or category X.

The most common contraception used in these women is the combined oral contraceptive. Ensuring the adequacy of contraception when given, and especially in women taking other medications that are known or unknown teratogens is important, as 40 % of unintended pregnancies occur in women using contraception and 90 % of these are due to inconsistent or incorrect use (Kost et al. (2008), Steinkellner et al. (2010). A survey of hospital doctors in the US identified that barriers to contraceptive counselling when prescribing included a lack of reimbursement for such counselling, as well as poor knowledge of both teratogens and contraceptives (Eisenberg et al. (2010).

Contraceptive status should be recorded with the prescribed medicines and strenuous efforts made to maximise the efficacy of oral and other contraception where it is used. Women should be warned regarding pregnancy on the initiation of any prescribed medicine, and this should be recorded in the medical record. Women using any prescription medicine should be strongly advised to re-consult their primary care doctors regarding medicine use before contemplating pregnancy.

Prescribing hormonal contraceptives is covered in some the detail in other chapters of this book: here I will only focus on issues relating to providing contraceptive advice and medicines/devices in primary care in these (and any) circumstances. Two general principles apply. The first is to maximise efficacy of contraception when taking other prescription medicines long term by adequate instruction and reminders. The second is to minimise risk. Prescribing contraceptives would be one of the most common prescriptions provided for women in primary care, and illustrates a general principle that is extremely important. Where the decision is made to prescribe hormonal contraception, or any medicine to women, it should be done from a perspective of comparative safety. While justification of the risk of venous thromboembolism (VTE) using hormonal contraception is made on the basis of the risk of VTE in pregnancy, this cannot be used to justify using a product with excess risk compared with those that carry less risk. Useful resources are available and should guide these decisions, for example in this case those that group contraceptives by comparative risk of venous thromboembolism (Table 14.2).

Table 14.2

Risk tables: birth control pills: venous thromboembolic risks

	Birth control pill ¹	Estrogen	Progestin	Adjusted annual relative clot risk vs. non use (95 % CI) ²	Adjusted annual relative clot risk vs. Levonorgestrel-containing pills ³
Progesterone-only pills	Micronor (28)	–	Norethindrone 0.35 mg	0.6 (03–1.1)	–
Levonorgestrel-containing combined estrogen-progestin pills	Alesse (21 + 28)	20 mcg	Levonorgestrel 0.1 mg	2.2 (1.7–2.8)	–
	Aviane (21 + 28)	20 mcg	Levonorgestrel 0.1 mg	2.2 (1.7–2.8)	–
	Min-Ovral (21 + 28)	30 mcg	Levonorgestrel 0.15 mg	2.2 (1.7–2.8)	–
	Portia (21 + 28)	30 mcg	Levonorgestrel 0.15 mg	2.2 (1.7–2.8)	–
	Seasonale/Seasonique	30 mcg	Levonorgestrel 0.15 mg	2.2 (1.7–2.8)	–
	Triquilar (21 + 28)	30/40/30 mcg	Levonorgestrel 0.05/0.075/0.125 mg	2.3 (1.9–2.8)	–
Norethindrone-containing combined estrogen-progestin pills	Brevicon 0.5/35 (21 + 28)	35 mcg	Norethindrone 0.5 mg	1.6 (0.8–2.9)	0.8 (0.4–1.6), NS
	Brevicon 1/35 (21 + 28)	35 mcg	Norethindrone 1 mg	1.6 (0.8–2.9)	0.8 (0.4–1.6), NS
	Loestrin 1.5/30 (21 + 28)	30 mcg	Norethindrone acetate 1.5 mg	1.6 (0.8–2.9)	0.8 (0.4–1.6), NS
	Minestrin 1/20 (21 + 28)	20 mcg	Norethindrone acetate 1 mg	1.6 (0.8–2.9)	0.8 (0.4–1.6), NS
	Ortho 0.5/35 (21 + 28)	35 mcg	Norethindrone 0.5 mg	1.6 (0.8–2.9)	0.8 (0.4–1.6), NS
	Ortho 1/35 (21 + 28)	35 mcg	Norethindrone 1 mg	1.6 (0.8–2.9)	0.8 (0.4–1.6), NS
	Ortho 7/7/7 (21 + 28)	35 mcg	Norethindrone 0.5/0.75/1 mg	1.6 (0.8–2.9)	0.8 (0.4–1.6), NS
	Synphasic (21 + 28)	35 mcg	Norethindrone 0.5/1 mg	1.6 (0.8–2.9)	0.8 (0.4–1.6), NS
Norgestimate-containing combined estrogen-progestin pills	Cyclen (21 + 28)	35 mcg	Norgestimate 0.25 mg	2.6 (2.2–3.0)	1.2 (0.9–1.6), NS
	Tri-Cyclen (21 + 28)	35 mcg	Norgestimate 0.18/0.215/0.25 mg	2.6 (2.2–3.0)	1.2 (0.9–1.6), NS
	Tri-Cyclen Lo (21 + 28)	25 mcg	Norgestimate 0.18/0.215/0.25 mg	2.6 (2.2–3.0)	1.2 (0.9–1.6), NS
	Apri (21 + 28)	30 mcg	Desogestrel 0.15 mg	4.2 (3.6–4.9)	2.2 (1.7–3.0), p < .001
	Diane-35 (acne)	35 mcg	Cyproterone acetate 2 mg	4.1 (3.4–5.0)	2.1 (1.5–3.0), p < .001
	Linessa (21 + 28)	25 mcg	Desogestrel 0.1/0.125/0.15 mg	4.2 (3.6–4.9)	2.2 (1.7–3.0), p < .001
	Marvelon (21 + 28)	30 mcg	Desogestrel 0.15 mg	4.2 (3.6–4.9)	2.2 (1.7–3.0), p < .001
	Ortho-Cept (21 + 28)	30 mcg	Desogestrel 0.15 mg	4.2 (3.6–4.9)	2.2 (1.7-3.0), p < .001
	Ovral	50 mcg	D-norgestrel 0.25 mg	3.5 (2.5–5.1)	Data not available
	Yasmin (21 + 28)	30 mcg	Drospirenone 3 mg	4.5 (3.9–5.1)	2.1 (1.6–2.8), p < .001
	Yaz (28)	20 mcg	Drospirenone 3 mg	4.8 (3.2–7.3)	2.1 (1.6–2.8), p < .001
	Demulen 30 (21 + 28)	Data not available (sometimes classified as lower risk)
Non-oral hormonal contraception	Transdermal combined *contraceptive patches			7.9 (3.5–17.7)⁴	2.3 (1.0–5.2)***
	Vaginal ring**			6.5 (4.7–8.9) p < .001⁴	1.9 (1.3–2.7)****

Adapted with permission from Mintzes B, Monk T www.pathwaysbc.ca

Notes

Baseline clot risk for woman under 35 on no bcp: 2.2/10,000⁵

Baseline clot risk for woman age 35–49 on bcp: 14.8/10,000⁵

Baseline clot risk during pregnancy (age not specified): 7–27/10,000⁶

Baseline clot risk, early postpartum (age not specified): 40–65/10,000⁶

Non oral contraceptives:

*When compared with oral contraceptives containing the corresponding progestogen (norgestimate), the adjusted rate ratio was 2.2 (1.0–5.0)

**When compared with oral contraceptives containing the corresponding progestogen (norgestimate), the adjusted rate ratio was 1.8

***Before adjustment for length of use 2.3 (1.0–5.2)

****Before adjustment for length of use 2.0 (1.4–2.9)

1. Brand names are Canadian and may differ between countries

2. Lidegaard et al. BMJ 2011; 343: d6423; based on full population data for Denmark, 2001–2009; eight million women-years of exposure, adjusted for age, year, and education levels

3. Lidegaard et al. BMJ 2011; 343: d6423; based on full population data for Denmark, 2001–2009; eight million women-years of exposure, adjusted for age, year, education levels, and length of use

4. Lidegaard et al. BMJ 2012; 344: e2990; based on all non-pregnant women from Denmark, free of previous thrombotic disease or cancer, 2001–2010

5. Lidegaard et al. BMJ 2011; 343: d6423; rates derived from Table 14.1, crude incidence per 10,000 women-years

6. US FDA Drug Safety communication: updated information about the risks of blood clots in women taking birth control pills containing drospirenone, (4-10-2012), available at: www.fda.gov/Drugs/DrugSafety/ucm299305.htm

Fragmented prescribing by multiple prescribers increases the risk of potentially teratogenic drugs being prescribed – with multiple drugs prescribed and dilution of responsibility, and the prescriber of a potentially teratogenic medicine may not feel it is their responsibility to provide the contraceptive advice needed – in a survey of internal medicine specialists in the United States most (88 %) felt it was the responsibility of primary care physicians to provide contraceptive advice and counselling (Eisenberg et al. 2010). ‘Most Responsible Provider’ is a fashionable term and it is the primary care clinician who is usually the patient’s Most Responsible Provider. General advice and warnings are needed from the primary care clinician. This is despite the origin of prescriptions from a different source as the medication prescriber may not perceive it to be his/her responsibility and the woman may think an absence of warning and counselling implies safety.

Treatment of Urinary Tract Infections in Women in Primary Care

Women also suffer in greater proportion from some short term illnesses commonly treated in primary care where medicines are prescribed. Urinary tract infection is one example. In this case there are wider community responsibilities to consider. Prescribing antibiotics for UTI is for reducing symptom duration rather than microbiological ‘cure’. Around 10 % of women will suffer from a lower urinary tract infection in a year, 50 % in a lifetime, with around a third of these occurring before age 24 (Foxman 2003). This exposes a large proportion of the community to whichever antibiotic is chosen first line. The risk of driving antibiotic resistance in the chosen class is high so responsible choice is important.

Research indicates that empiric prescribing is justified on the basis of symptoms (Richards et al. 2005). It also indicates that the resistance rates quoted in laboratories overstate the true resistance rate (Richards et al. 2002). Low side effect, narrow spectrum antibiotics such as notrofurantoin and the most appropriate, with efficacy measured in terms of clinical symptoms (BPAC 2011). A recent paper indicates that in older patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers, co-trimoxazole is associated with an increased risk of sudden death. This is probably related to trimpethoprim-induced sudden hyperkalemia. Other drugs such as nitrofurantoin should be chosen first line where a woman is taking an ACE or an ARB, or potassium should be monitored (Fralick et al. 2014). This preserves broader spectrum and more risky drugs for more serious infections. Drugs such as fluoroquinalones are increasingly used, however they have side effects more significant than the symptoms they treat in this instance – the risk of tendon rupture increases with even short term use (Movin et al. 1997; McGarvey et al. 1996).

Medicines for Healthy Women

There are many medicines that can be and are given to currently healthy, asymptomatic women. Some of this kind of prescribing is medically driven, for example for primary prevention of future disease such as cardiovascular disease, and some generated by requests from women, often from pressure to weigh less or look younger. In countries where direct to consumer advertising is allowed these requests for ‘lifestyle’ medicines may be generated by advertisements, in other countries more subtle media presence of commercial interests in magazines and newspaper press releases or advertorial articles may stimulate requests as detailed previously.

It is important in discussions on these medicines to separate the pressure to prescribe for social or commercial or even state driven reasons (springing from a desire to reduce the economic burden of health care) with a population based approach to prescribing, from what the evidence suggests is in the best interest of the woman sitting in the consultation room. As discussed earlier in this chapter, publications assessing the evidence for benefit in women indicate that statins are of no benefit in primary prevention and less benefit generally to women (Redburg and Roberts). Similarly anti-hypertensives may carry more risks for women as detailed.

Archie Cochrane’s comments on such screening and subsequent treatment of the healthy provide a succinct summary of the primary care practitioner’s responsibility:

We believe that there is an ethical difference between everyday medical practice and screening. If a patient asks a medical practitioner for help, the doctor does the best he [or she] can. He [or she] is not responsible for defects in medical knowledge. If, however, the practitioner initiates screening procedures he [or she] is in a very different situation. He [or she] should, in our view, have conclusive evidence that screening can alter the natural history of the disease in a significant proportion of those screened. (Cochrane and Holland 1971)

Overactive bladder for example was a condition name invented by a public relations campaign for a pharmaceutical company (Toop and Richards 2003) with demand stimulated by a planned campaign targeting women and physicians with checklists and advertisements. The drug advertised offers no clinically significant benefit (Therapeutics Initiative 2005) and going to the toilet frequently is not a medical condition.

Almost all medications for weight loss have had subsequent safety concerns about stimulating effects on the cardiovascular system and, in the case of ‘Fen-Phen’, structural abnormalities (Drolet et al. 2007; CDC 1997). Some weight reduction medicines such as sibutramine (Reductil^©) and Fen-Phen have been withdrawn from the market due to an unacceptable risk benefit profile (Drolet et al. 2007; CDC 1997). Few, if any, have offered sustained weight loss. This experience ought to stimulate prescriber caution with any new products in this group.

A woman is better served in addressing lifestyle issues by lifestyle modulation before chemoprevention where the evidence is less certain. Healthy public policy is the best way to address unhealthy environments and health problems that result from economic disparity.

Non-pharmacological Approaches to Treatment: The Safest Prescribing

The practice of medicine is increasingly synonymous with the giving of medicines. This is further amplified in the prescribing patterns for women. For most common complaints and diagnoses, women receive prescriptions more often than men (Verbrugge and Steiner 1985).

The safest prescribing is of effective non-drug alternatives. It is easy to forget the efficacy and safety of alternate strategies among the flooding of the literature and hype to doctors and patients associated with pharmaceutical company research on their products. It is also easy to forget that most people taking long term medicines are not benefiting from them (in order for half to benefit the NNT must be two or less and there are few drugs for chronic disease or risk that meet this threshold). This means that most patients are taking risks without hope of benefits.

According to a CDC report summarising US data sources, 15 % of women in the reproductive years suffer from depression and 7 % from ‘hypertension’, while 49 % get insufficient exercise and 32 % are obese (CDC 2011). For these women, exercise and healthy eating is likely to offer greater gains at less risk than pharmacological treatment. If all women were of normal weight, exercised daily, and maintained a healthy diet, this report estimates number of women with hypertension could be reduced by approximately 50 % (CDC 2011).

Exploring effective and safe non pharmacological approaches to treatment seems warranted. This would seem even more justified where there are multiple morbidities that might be reduced, or the medication burden reduced. Unfortunately the nature of primary care means that the more medical conditions there are to discuss, the less likely routine health maintenance is addressed (Katerndahl et al. 2011). This creates a paradoxical effect where patients who are most likely to benefit from strategies such as improved diet and exercise across their multiple conditions are least likely to receive support with this. This is not because of a fault of their doctor, but rather the fault of a system that does not allow for adequate time to be given to complex primary care that is needed.

Improving the Data for Prescribing for Women

Given the paucity of evidence from RCTs for differential effects of medicines in women, one of the key tools primary care clinicians have is in contributing to the evidence base to inform prescribing for women. Doctor and patient reporting of adverse drug effects is the main way the evidence on side effects is gathered once a drug is on the market. Most countries allow direct reporting by doctors, other health professionals and the pharmaceutical industry to the regulator through such agencies as the FDA (US), Health Canada (Canada), the MHRA (the Yellow Card system in the UK). Many other countries, including Australia and New Zealand, also have long-standing spontaneous reporting systems in place.

Patient direct reporting to the national pharmacovigilance centre and/or regulator is also allowed in a few countries and two reviews have concluded it is equally reliable, though more time consuming to report, and that patients are more likely to directly report drug adverse reactions when they feel their health care provider has not listened to their concerns (Herxheimer et al. 2010; Blenkinsopp et al. 2007). One paper on patient reporting of statin side effects enquired about physician response, and found many patients experienced physician denial of the side effects indicating that doctor reporting may contain ascertainment bias (Golomb et al. 2007).

Patient direct reporting of side effects can also be made online through RxISK.org, a global pharmacovigilance website that has a searchable central database that combines direct patient reports with publicly accessible pharmacovigilance datasets including the FDA and Health Canada. Entering information does double duty – providing a clinical resource by giving an individual assessment of the likelihood of causality when a woman presents with symptoms that may represent a drug side effect using a causality algorithm and automatically searching the databases for similar reports. At the same time this data is recorded in the RxISK searchable dataset and prepopulates forms to be sent to individual country regulators such as the MHRA, FDA, Health Canada and others. This alertness to and recording of the observations of women and those who treat them is essential, especially in the absence of specific and publicly available raw data from clinical trials. Pharmacovigilance data is available disaggregated by sex and clinicians and women contributing to them increase the data to inform prescribing for women,

Direct observation and reporting of the effects of drugs on patients in the community such as this is how the effects of thalidomide were discovered, and thalidomide provides an illustration of why these post-marketing data are so important, beyond the data from RCTs that are sufficient for licensing: Thalidomide was the first drug ever to be pronounced effective on the basis of randomised controlled trial (carried out by a pharmacologist named Louis Lasagna who was later responsible for pushing for the inclusion of randomised controlled trials as a basis for licensing of drugs by the FDA). The serious side effects were not detected.

Conclusions

Women are more likely to be prescribed medicines, and more likely to suffer from their side effects. Most trials are not carried out in the primary care population, where benefits are generally less than in secondary care populations with more severe disease or risk. Many medicines have not been extensively tested on women and most trials that do include women do not report efficacy and safety broken down by gender.

In the primary care environment of prescribing multiple medicines for women based on an uncertain evidence base, the best adjunct to providing the best care for women is clinical observation. New drugs to the market should be prescribed even more cautiously in women than in the general population. Screening and investigation likely to result in possible over-diagnosis and subsequent prescription of a medicine should be avoided. Dosing should start at the lowest possible dose of a medication – lower than the standard recommendation and titrated up according to effect where possible. This requires vigilance in monitoring both beneficial and harmful drug effects and titrating the dose for the individual to levels that may not reflect the ‘standard dosing’ but may be most appropriate for that individual woman.

When prescribing in comorbidity, efforts should be made to limit the numbers of medicines to five or less. This decision should be guided by patient priorities for care, potential for benefit and potential for adverse effects and interactions. Women are more vulnerable to polypharmacy and its adverse effects. There is evidence for benefit of trials of stopping or reducing the dose of medicines in this case. Legacy drugs such as SSRIs and bisphosphonates, which have time limited value, should have dates set for active discontinuation when prescribing is first initiated and these should be discussed with the patient. When prescribing multiple medicines in comorbidity, regular planned review and monitored drug pauses should be trialled to determine ongoing need and to uncover any adverse effects. Prescribing effective non pharmacological treatments should be done wherever possible.

Prescribing medicines is one of the most common and dangerous things we do in medical care. Adverse drug effects are among one of the leading causes of death in most countries in the developed world: for example a Swedish population based study indicates they are the seventh most common cause of death in Sweden and hospital based studies in the US suggest they are the fourth to fifth leading cause (Wester et al. 2008; Lazarou et al. 1998) in most countries in the developed world. This fact is largely lost amidst the highlighting of disease epidemics causing death. Around a third of these adverse drug effects are avoidable. To provide good care in prescribing medicines for women we must be careful, and prescribe from a position of comparative safety.

Take Home Messages

· Women are prescribed more medicines than men, and are more susceptible to adverse events, yet there is less evidence for safety and efficacy of prescription medicines in women than in men, and even less in the primary care setting.

· Dose information is usually not differentiated by sex, yet there is evidence that the equivalent dose may differ for women and men – starting at the lowest possible dose and titrating up if necessary is the safest approach in this circumstance.

· In healthy asymptomatic women a high level of certainty for benefit should be required before initiating a long term medicine. Prescribing in the best interests of the individual woman presenting to a primary care prescriber requires awareness of social, commercial and state pressures to prescribe on both prescribers and patients.

· Legacy drugs such as SSRIs, PPIs and bisphosphonates, which have time limited value, should have dates set for active discontinuation when prescribing is first initiated and these should be discussed with the patient.

· Primary care prescribers need to be alert to the fact that prescription drug overdose and abuse are substantial and increasing problems among women.

· When prescribing multiple medicines in chronic comorbidity, regular planned review and monitored drug pauses should be trialled to determine ongoing need and to uncover any adverse effects.

· When prescribing in comorbidity, efforts should be made to limit drugs to 5 or less

· Women taking medicines should be warned regularly regarding pregnancy and any need for tapering medication when stopping, and this should be recorded in the medical record.

· Women using any prescription medicine long term should be provided adequate effective contraception and strongly advised to re-consult before contemplating pregnancy. Contraceptive status should be recorded with the prescribed medicines and strenuous efforts made to maximise the efficacy of oral and other contraception where it is used.

· The safest prescribing is not to use medicines where there are effective non pharmacological treatments.

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