Letter from CAP

Concern over HPV vaccines

(Fri, 24 Dec 2010) 

THE Consumers Association of Penang is aghast that the relevant authorities, particularly the Health Ministry, have kept silent over the raging controversies on the rush to get young girls vaccinated against cervical cancer. There are many areas of concern over the human papillomavirus (HPV) vaccine which is said to prevent infection against certain species of human papillomavirus associated with cervical cancer, genital warts and some less common cancers.

Many countries are going slow on this vaccine because of many doubts raised. However, Malaysia is rushing into it. HPV vaccines, given in a series of three shots, are to make the body’s immune system produce antibodies against HPV types 16 and 18, which cause seven out of 10 cases of cervical cancer. The antibodies supposedly protect one from getting infected with HPV.

And yet the authorities are not giving the people any details. Even the type of vaccine used seems to be top secret. Two HPV vaccines are in the market: Gardasil and Cervarix. Which one is Malaysia using? And experts tell us that the regular Pap smear screening must be continued to be done even after vaccination because the vaccine only covers some high-risk types of HPV.

The World Health Organisation warned late last year that those vaccinated and do not continue with screening, such as Pap smear because they wrongly believe they are protected against cervical cancer, can raise the death figures, especially with the vaccine protection waning over time.

Some concerns have been raised by the US Centers for Disease Control and Prevention:

As of Sept 1, 2009, there were 15,037 Vaccine Adverse Event Reporting System (VAERS) cases of adverse events following Gardasil vaccination in the US. Of these reports, 93% were reports of events considered to be non-serious, and 7% were reports of events considered to be serious.

Reports on non-serious adverse events after Gardasil vaccination have included fainting, pain and swelling at the injection site (the arm), headache, nausea and fever.

VAERS defines serious adverse events as those that involve hospitalisation, permanent disability, life-threatening illnesses and death.

As of Sept 1, 2009, there have been 44 reports of death among females in the US who have received the vaccine.

CAP calls on the authorities to stop the vaccine programme until the people are clear about it. In September 2009, when the government announced its intention to vaccinate some 300,000 13-year-old-schoolgirls, we voiced our objections. We reiterate that inoculating schoolgirls with the vaccine is a symptomatic and simplistic solution to the problem of cervical cancer in children who may contract cervical cancer due to early sexual activity when instead, the root cause for contracting HPV - sexual relations with multiple partners; should be countered by education.

S.M. Mohamed Idris
President
Consumers Association of Penang

Menopausal hormone therapy association with breast cancer strengthened

In 2002, the Women's Health Initiative (WHI) randomized trial of placebo vs hormone therapy with estrogen and progestin was stopped early because of evidence of harm.¹ Sales of combined estrogen-progestin plummeted 32% between the period immediately before the study's release and the analogous period 1 year later, as the WHI trial had shown that hormone therapy increased a woman's risk of breast cancer and myocardial infarction.² The finding contradicted decades of case-control and observational cohort studies that had suggested that hormone therapy was associated with strong protective effects on the cardiovascular system. The WHI results also undermined a long and successful campaign by hormone replacement advocates to present hormone therapy as a panacea against heart disease, loss of femininity, and other perils of aging. In addition, the WHI documented numerous other negative effects of hormone therapy, including an increased risk of stroke and pulmonary embolism,¹ which are not strongly associated with the timing of hormone therapy initiation. Ultimately, the only long-term benefit of hormone therapy that the US Food and Drug Administration (FDA) allows the manufacturer to claim is reduction of risk of osteoporotic fractures.³

That breast cancer rates in the WHI increased among women receiving hormone therapy was not surprising. Epidemiological and biological studies had anticipated the effect,⁴ although the magnitude of risk was not known until the WHI, which showed that the effect of hormone therapy on breast cancer risk was about the same as the deleterious effect on cardiovascular health. Several years after use of hormone therapy plummeted in the United States, breast cancer incidence also declined.⁵

Chlebowski et al⁶ report results of an 11-year follow-up of WHI estrogen-progestin trial participants that address many of these questions. The authors found that hormone therapy increases the frequency of breast cancer and that the breast cancers are on average more advanced and may be larger. The authors found no evidence that the cancers had favourable prognostic features, such as more frequently being estrogen receptor positive or lacking HER2 /neu gene amplification. If anything, the results suggest a trend in the direction of less favourable cancers. In addition, the authors found strong evidence that the rate of breast cancer death is increased by hormone therapy. It is also probable that the increase in breast cancer deaths due to hormone therapy has been underestimated in the current study and that with longer follow-up, the deleterious effect will appear larger. This suggestion is based on several observations: the mortality curves appear to still be separating at the end of the current follow-up (Figure 4A in the article); the difference in cumulative breast cancer incidence between women in the hormone therapy and placebo groups is widening (Figure 2 in the article), which will ultimately lead to more deaths; and the breast cancers diagnosed among women who received hormone therapy are associated with a poorer prognosis.

Based on present data, the authors project that approximately 1.3 additional deaths from breast cancer per 10 000 person-years of follow-up have already occurred among the women who received hormone therapy in the study. Since this number is relatively small, clinicians might conclude that a brief period of hormone therapy for relief of menopausal symptoms is safe. Such a view would be consistent with some professional guidelines⁷ and with the FDA-approved label for combined estrogen-progestin therapy.³ However, the study by Chlebowski et al⁶ does not address the effect of short periods of hormone therapy on breast cancer risk (or other disease risk), and the current estimate of the deleterious effects of hormone therapy may be underestimated.

Therefore, the available data dictate caution in the current approach to use of hormone therapy, particularly because one of the lessons from the WHI is that physicians are ill-equipped to anticipate the effect of hormone therapy on long-term health. Clinicians who prescribe brief courses of hormone therapy for relief of menopausal symptoms should be aware that this approach has not been proven in rigorous clinical trials and that the downstream negative consequences for their patients are of uncertain magnitude. Given the substantial population of women who seek relief from menopausal symptoms and the large potential burden of disease that could be created if medications given to alleviate symptoms today cause cancer and other deaths tomorrow, it seems that additional randomized trials are needed specifically to determine whether lower doses or shorter durations of hormone therapy could alleviate menopausal symptoms without increasing cancer risk.

References

1. Rossouw JE, Anderson GL, Prentice RL; et al, Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

2. Majumdar SR, Almasi EA, Stafford RS. Promotion and prescribing of hormone therapy after report of harm by the Women's Health Initiative. JAMA. 2004;292(16):1983-1988.

3. US Food and Drug Administration. Prempro prescribing information. 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020527s045lbl.pdf

4. Key TJA, Pike MC. The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol. 1988;24(1):29-43. 

5. Chlebowski RT, Kuller LH, Prentice RL; et al, WHI Investigators. Breast cancer after use of estrogen plus progestin in postmenopausal women. N Engl J Med. 2009;360(6):573-587.

6. Chlebowski RT, Anderson GL, Gass M; et al, WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA.2010;304(15):1684-1692.  

7. US Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the US Preventive Services Task Force. Ann Intern Med. 2005;142(10):855-860.

Edited by Hanifullah Khan from  Bach PB. Postmenopausal Hormone Therapy and Breast Cancer: An Uncertain Trade-off. JAMA  2010;304(15):1719-1720. doi:10.1001/jama.2010.1528

Two Cervical Cancer Vaccines

1. Two prophylactic HPV vaccines, Cervarix™ (GlaxoSmithKline) and Gardasil™ (Merck) have been licensed for use. Both have been tested in large randomised placebo-controlled trials involving thousands of women from different countries across the world.
2. Impressive protection against persistent vaccine-specific HPV infection has been demonstrated over short- to medium-term follow-up periods. Long-term follow-up data are still required to answer the question of longevity of immune protection and whether booster vaccination(s) will be necessary, and at what time interval.
3. Because of ethical and consent issues, efficacy cannot be determined among pre-adolescent girls, but is assumed by extrapolating data from the young women involved in the original vaccination trials. These suggest higher immune responses following vaccination among young adolescent girls (and boys) when compared with young adults, suggesting that vaccination at this younger age may result either in longer sustained immunity, improved long-term clinical efficacy, or both.
4. It is difficult to assess the impact of an immunisation strategy when many factors are still unknown. 
5. The coverage for the third dose is critical as the vaccine is locally painful and girls may be reluctant to complete the course.
6. The vaccines remain prohibitively expensive - universal HPV vaccination is unlikely in resource-poor countries lacking organised screening programmes, where cervical cancer remains a major cause of cancer-related death in women, and vaccination would be most beneficial. Those countries providing HPV vaccination at the moment have more efficient cervical screening programmes and lower cervical cancer rates than those yet to introduce it.
7. Merck was the first of two pharmaceutical companies to license its vaccine in October 2006, giving it a commercial head start. This quadrivalent vaccine confers immunity against the two oncogenic strains of HPV responsible for 70% of cervical cancers (HPV 16 and 18), as well as two strains that together cause 90% of genital warts (HPV 6 and 11). To many, a vaccine that protects against four strains has appeared to be inherently ‘better’ than one protecting against two strains.15 The bivalent vaccine Cervarix did not become available until almost a year later, in September 2007. Cervarix protects against HPV types 16 and 18, but does not prevent genital warts.
8. Insofar as Cervarix does not prevent genital warts, its use may amount to a ‘missed opportunity’. Genital warts are a very common sexually transmitted viral infection responsible for unsightly lesions that are both difficult and costly to treat. Women with genital warts also risk spread of the infection to the respiratory tract of their newborn infant during childbirth. Recurrent respiratory papillomatosis is a rare, but chronic, debilitating disease characterised by hoarseness, stridor and respiratory distress in the newborn, and requires lifelong repeated surgical intervention and prolonged hospital stays, even causing death in a minority of cases.
9. Published data do not distinguish either vaccine as superior in terms of clinical effectiveness or toxicity. However, recent data released by GlaxoSmithKline from their head-to-head comparison of the two vaccines reported that Cervarix induced significantly higher HPV 16 and 18 serum neutralising antibody titres, as well as higher levels of neutralising antibodies in cervicovaginal secretions and circulating HPV 16 and 18-specific memory B-cells. These results would suggest that a longer duration of protection against HPV infection may be conferred by Cervarix. Declining antibody levels post-vaccination may not, however, indicate a loss of protection, as immunological memory may persist at low levels, and is difficult to measure. Natural viral challenge may be sufficient to ‘boost’ declining serological responses, although booster vaccination is superior.
10. Future cervical screening. Cervical cancer develops after an infection period of a decade or more, and up to 30% of cervical cancers are caused by HPV types not included in either vaccine. Although some degree of cross-protection against similar high-risk HPV types has been presumed from trial data, vaccinated women are still clearly at risk of contracting other oncogenic HPV types that can cause cervical cancer, and cervical screening will still be necessary, even for vaccinated women.
11. Safety scares. In general, both Cervarix and Gardasil appear to be safe and well tolerated. Injection site adverse events, including pain, swelling and redness, have been reported more frequently by women receiving the vaccine, compared with those receiving placebo in clinical trials. Cervarix is recognised to be a more painful inoculation than Gardasil, but even so, most side effects disappear within the first day or two.
12. There have been no deaths attributable to either vaccine in any of the clinical trials to date. Pregnancy and congenital anomaly data have been reported for Gardasil, but not for Cervarix. Higher rates of congenital anomalies unrelated to type have been observed.
13. Maintaining high vaccine coverage. Interim results for the uptake of the third dose has shown a drop in coverage from 83% at the first dose to 74% for dose 3. Whether girls who receive only the first two doses of the vaccine will show sufficient immunity against HPV to prevent subsequent infection remains unclear.
14. The effect of mistimed doses is not fully understood. Data from hepatitis B vaccination studies suggest that longer intervals between second and third doses of the HPV vaccine may not be detrimental to the strength of the immunity generated, presumably as long as HPV exposure does not occur during the delay.

No benefit from GnRH analogue pretreatment for hysteroscopic submucous fibroid resection

Uterine fibroids are the most common benign tumours of the female reproductive tract. On the basis of their location, they can be divided into submucous, intramural or subserosal. Fibroids tend to grow in an estrogenic environment as evidenced by the reduction in size during menopause or in a medically induced hypoestrogenic state, such as with Gonadotrophin Releasing Hormone (GnRH) analogue therapy. Hysterectomy remains the only method of definitive treatment for symptomatic fibroids. However, conservative treatment may be desirable in many instances, chief among which would be the maintenance of child-bearing capability. Other reasons for keeping one’s uterus include better sexual functioning and avoidance of surgery, whether by choice or clinical reasoning.

This conservatism has lead to a proliferation of less invasive methods pursuing management of fibroids without recourse to surgery. Medical therapy provides only temporary relief of variable duration with repeat treatments a nuisance. Amongst the various radiological interventions, uterine artery embolization is an effective procedure, though not an ideal solution if future fertility is desired.(1) Hysteroscopic resection is quite feasible for treatment of submucosal fibroids, and the subject of our current attention.

Whether surgical or otherwise, all these methods can be hampered by complications such as bleeding, obstructed views and inadequate resection during the procedure. In order to minimize these risks, shrinking the fibroids to a more manageable size prior to the procedure offers a logical and practical proposition. GnRH analogue therapy has been advocated as a means to this end for some time now. Advantages of such pretreatment include reduction of fibroid size, bleeding and operating time and visual improvement during the procedure. Disadvantages, it has been said, include non-identification of tumour and tumour recurrence post-procedure. Many investigations in the past have set out to settle this issue once and for all but no definitive data has yet emerged.

The latest study to address this issue involved 47 reproductive-aged women with symptomatic submucosal fibroids randomly assigned to receive 3 months of depot goserelin or placebo injections prior to hysteroscopic resection (2). Sample size was calculated on the basis of an expected complete resection rate of about 50% without pretreatment and an improvement in resection rate to 92% with use of GnRH analogue. The primary outcome measure was the rate of complete resection of the fibroids.

Baseline characteristics and the number and size of submucous fibroids were well balanced in the study groups. Overall, 75% of the women had complete fibroid resection; this frequency was similar in both groups. Fibroid size and degree of intramural involvement were negatively associated with the frequency of successful complete resection. The duration of the procedure, the amount of distention fluid used, and the complication rates (excessive fluid deficit, bleeding, and perforation) were similar in the 2 groups. A similar proportion of women reported symptom improvement, and the need for second surgeries was not different between the 2 groups. On the basis of their findings, Mavrelos and colleagues concluded that preoperative use of GnRH analogues does not improve the outcome of hysteroscopic resection of submucous fibroids.

Evaluation of the outcomes of such trials requires the consideration of many factors. Although the study design seems sturdy, the number of patients involved in this case is not life-defining. A much larger number is required to provide significance. Surgical expertise plays an important part and a fairly high complete resection rate in the placebo arm might reflect the presumed above-average experience of the single surgeon involved. Results might differ with less experienced surgeons or in patients who truly benefit from GnRH analogue pretreatment. Since this study only evaluated women with submucous fibroids, the results obviously cannot be applied to fibroids of other persuasions. Thus, although this study did not find a benefit with GnRH therapy prior to hysteroscopic fibroid resection, use of this therapy should still be considered on an individual basis.

References

1. Freed MM, Spies JB. Uterine artery embolization for fibroids: a review of current outcomes. Semin Reprod Med. 2010;28:235-241. 

2. Marvelos D, Ben-Nagi J, Davies A et al. The Value of Pre-operative Treatment With GnRH Analogues in Women With Submucous Fibroids: A Double-Blind, Placebo-Controlled Randomized Trial. Hum Reprod. 2010;25:2264-2269

FDA approves novel folate OCP

The US Food and Drug Administration (FDA) on 25 September 2010 approved a novel oral contraceptive that is formulated to provide both contraception and reduce the risk for neural tube defects in their offspring if and when they give birth. The new contraceptive, Beyaz (Bayer HealthCare Pharmaceuticals), contains levomefolate calcium, a metabolite of folic acid. Prepregnancy folate supplementation has been associated with a decreased risk of fetal neural tube defects. Thus arises the recommendation that women of childbearing age supplement their diet with folate. This is a logical step since women may become pregnant during oral contraceptive use or shortly after discontinuation. The approval is based on the already-approved oral contraceptive drospirenone/ethinyl estradiol (Yaz, Bayer HealthCare Pharmaceuticals), which contains the same doses of estrogen and progestin.

Apart from the primary indication of contraception, Beyaz is also approved for the treatment of symptoms of premenstrual dysphoric disorder (PMDD), acne vulgaris and the prevention of fetal neural tube defects in women who choose an oral contraceptive as their method of contraception.

According to the FDA (www.fda.gov), the primary efficacy study for Beyaz was a multicenter, double-blind, randomized, controlled U.S. trial in 379 healthy women aged 18 to 40 who were treated with Beyaz or YAZ alone for up to 24 weeks. Beyaz was found to increase folate levels in women. In a German study of Beyaz, folate levels remained elevated for several weeks following discontinuation of Beyaz.  Safety and efficacy data for contraception, PMDD, and acne indications were obtained from previous YAZ clinical trials.

The clinical trials of Beyaz did not yield any findings that would suggest it differs from Yaz in terms of its overall safety profile. It is expected that the most common adverse events for Beyaz will be the same as those for Yaz. Adverse effects most frequently reported by users of combined oral contraceptives are irregular uterine bleeding, nausea, breast tenderness, and headaches.

New propylthiouracil warnings change face of hyperthyroid treatment in pregnancy

Untreated hyperthyroidism in pregnancy places the mother and child at an elevated risk for a number of adverse outcomes, including preeclampsia and congestive heart failure. Because radioactive iodine is not a viable option during pregnancy, and surgery is risky, health care professionals are limited to propylthiouracil and methimazole. 

Recent warnings from the FDA, however, have addressed serious adverse reactions to propylthiouracil, including severe liver injury and acute liver failure — some fatal — leading the agency to recommend reserving use for patients who cannot tolerate other available treatments. It has been known since the 1940s that PTU can cause severe, potentially life-threatening hepatotoxicity. While this risk is not necessarily new to endocrinologists, there has recently been a push to recognize it as a potential problem 

Physicians are faced with an additional challenge in treating pregnant women with hyperthyroidism because of risks for birth defects observed with the commonly used drug methimazole. Experts, professional guidelines and the FDA currently recommend PTU as the treatment of choice before and during the first trimester of pregnancy. 

A study published in the Journal of Clinical Endocrinology & Metabolism in June revealed that methimazole is now the most commonly prescribed antithyroid treatment. Prescriptions for methimazole increased ninefold between 1991 and 2008, from 158,000 to 1.36 million per year, and the number of prescriptions has surpassed PTU as the most frequently prescribed antithyroid drug. In the study, women of childbearing age were the only demographic for which methimazole prescriptions decreased. 

Risks of therapy 

Of the 4 million pregnancies in the United States each year, 4,000 women are treated with antithyroid drugs and, until recently, most were prescribed PTU. Although in-depth data on hyperthyroid pregnancies are generally unavailable, it is estimated that four pregnant women per year will develop severe hepatic issues linked to PTU use, according to information provided by the FDA. In June 2009, the FDA released a black box warning highlighting hepatic dangers associated with PTU treatment, including serious liver injury, liver failure and death in adults and children. The warning was based on 32 cases of serious liver injury — 10 in children — which resulted in 13 deaths and 11 liver transplants. According to the FDA alert, methimazole was also linked to serious liver injury but to a lesser extent: five adult cases resulting in three deaths. 

The FDA updated its warning in April 2010 and recommended reserving use of PTU for those who cannot tolerate other treatments. The agency also required that a medication guide be distributed to each patient who fills a prescription for PTU. PTU had always been the preferred treatment in pregnancy over methimazole in the United States because it was thought from early studies that it did not cross the placenta to the same extent as methimazole. That has been proven wrong over the last 10 years. Recent studies, such as one published by Mortimer and colleagues in JCEM in 2007, have shown that PTU and methimazole have similar placental transfer kinetics. 

The original rationale for PTU no longer exists. However, PTU is still preferred, but not because of the reason initially thought; rather, it is now because of rare reports of birth defects associated with methimazole. Although the primary dangers of PTU treatment involve hepatic injury to the mother, the dangers of methimazole are concentrated on the developing fetus. The risks of methimazole include embryopathies such as aplasia cutis congenita, choanal atresia, esophageal atresia and tracheoesophageal fistula. According to the most recent FDA warning, congenital malformations were reported approximately three times more often with prenatal exposure to methimazole vs. PTU: 29 cases vs. nine cases. In addition, a distinct and consistent pattern of congenital malformations was observed with methimazole use. Developmental abnormalities such as cutis aplasia can occur with methimazole use early in the first trimester. However, these abnormalities are quite rare. It is not clear what the association is between methimazole and embryopathy due to lack of substantial data from large-scale studies. What is known is that based on several studies that looked at large cohorts of people, children exposed in utero to methimazole were at a greater risk for embryopathy compared with the general population. However, just how frequently it occurs remains unknown. 

It has been postulated that perhaps the embryopathy risk is not necessarily due to methimazole but rather the hyperthyroidism itself, according to a study cited by Mandel that was published in theAmerican Journal of Genetics in 2008. Barbero and colleagues conducted the multicenter, case-control study to compare the frequency of maternal hyperthyroidism treated with methimazole during pregnancy in children with choanal atresia. According to the results, prenatal exposure to methimazole was identified in 10 of 61 cases (16.4%) compared with two of 183 (1.1%) in a control group (OR=17.75; 95% CI, 3.49-121.40). The researchers concluded that prenatal exposure to maternal hyperthyroidism treated with methimazole appears to be associated with choanal atresia. Based on the cases and a critical literature review, they proposed that the mother’s disease might be the causal factor, and not the methimazole treatment. 

Combination treatment 

To avoid overt hyperthyroidism and adverse effects to the mother and baby, many experts and the FDA suggest a patchwork solution: treatment with PTU during the first trimester and, after organogenesis, a switch to methimazole. Guidelines from the American Thyroid Association and The Endocrine Society recommend: “Because available evidence suggests that methimazole may be associated with congenital anomalies, PTU should be used as a first-line drug, if available, especially during first-trimester organogenesis. Methimazole may be prescribed if PTU is not available or if a patient cannot tolerate or has an adverse response to PTU.” There should not be any methimazole-related birth defects after the first trimester. 

But, the transition from PTU to methimazole presents a unique set of problems. One worry is that after managing the patient’s hyperthyroidism with PTU, control may be lost during the switch to methimazole. If control is lost, it should be regained as soon as quickly as possible. 

Goals of therapy 

Ultimately, the risks for hyperthyroidism in pregnancy outweigh the risks for rare hepatic injury and embryopathy associated with these antithyroid drugs.Management with antithyroid drugs should be approached not with the goal of attaining mid-range thyroid hormone levels, but those at the upper limits of normal. It is preferred for the patient to be mildly clinically hyperthyroid. Subclinical hyperthyroidism does not have any adverse effect of pregnancy or delivery or the baby, but it reduces the amount of drugs given to patients. Not overtreating a woman during pregnancy is integral. 

Prepregnancy planning 

A further consideration regarding hyperthyroid pregnant women is that of prevention. The first question to ask a hyperthyroid patient is: When do you plan on conceiving? The best approach for a woman with Graves’ disease may be to avoid the entire question of methimazole and PTU during pregnancy, and render her hypothyroid before she conceives. If antithyroid drugs are necessary during pregnancy, a positive trend is that the condition generally improves with treatment. Autoimmune diseases such as Graves’ disease do tend to improve during pregnancy, so it is often possible to stop the treatment late in pregnancy. But each patient is different, and the doses will need to be adjusted and monitored. Other times, the physician will be able to wean the woman off of treatment late in the second trimester. However, after giving birth, some women may become hyperthyroid again, and some women will develop postpartum thyroiditis despite being fine during their pregnancy. 

Further treatment factors 

Although antithyroid drugs are ideally limited during pregnancy, other treatments are avoided altogether. Surgery and radioactive iodine — common treatments for general hyperthyroidism — are usually not feasible options during pregnancy. Radioactive iodine will cross the placenta, placing the fetus at an elevated risk for hypothyroidism, which is why it is never used during pregnancy.Surgery is also sparingly used. This option is something of a last resort to be turned to only if the patient is allergic or non-adherent to both methimazole and PTU, or if hyperthyroidism is uncontrolled. If necessary, it is safest in the second trimester. 

Summary recommendation 

Based on the currently available information, the best course of action to minimize the risk for mother and fetus is PTU treatment during the first trimester — strongly advising the patient on signs of liver injury and with careful monitoring — and then switch to methimazole following organogenesis. However, this recommendation is based on incomplete data and more studies in this area are needed.


Edited by Hanifullah Khan from an article by Matthew Brannon published in Endocrine Today on 1 September 2010

Editorial - The Avandia Saga Continues - NYTimes.com

A panel of expert advisers to the Food and Drug Administration delivered a confusing verdict on Wednesday after two days of hearings on the safety of the diabetes drug Avandia. A majority of the 33-member panel expressed concern that Avandia raises the risk of heart attacks compared with other diabetes drugs. But a majority also voted to leave the drug on the market anyway, with various degrees of restrictions or warnings. It will now be up to patients and their doctors to decide whether the risk is worth taking in particular cases.

In the crucial votes on Wednesday, the experts were asked to choose among five options for regulatory actions that the F.D.A. might take. Twelve voted to remove Avandia from the market. Ten voted to leave it on the market while further beefing up warning labels and adding restrictions on use, such as allowing only certain physicians to prescribe it or requiring special education for doctors and patients. Another 10 would settle for the current or somewhat stronger warnings. (One expert abstained.)

Some analysts see a victory for Glaxo, in that 20 of the panelists voted to retain the drug. But it is hardly reassuring that 22 of the panelists voted either for severe restrictions or complete banishment. The process doesn’t end here. The panel also voted to continue a large Glaxo-sponsored clinical trial to compare the cardiovascular risks of Avandia with those of Actos, its major rival, and with standard treatments for diabetes. Even if that trial is allowed to go forward, the results won’t be in for years. Right now, doctors and patients will have to think very hard before using a drug that a majority of these experts has deemed risky.

The clearest lesson to emerge from the hearings and other recent revelations is that GlaxoSmithKline, the maker of Avandia, can’t be trusted to report adverse clinical results fairly. The most troubling aspect of the Avandia saga is evidence — from internal company documents and investigations by a Senate committee and an F.D.A. investigator — that Glaxo sought to hide emerging indications of Avandia’s heart risks. Glaxo failed to report the results of a 1999 study that showed Avandia might be riskier for the heart than a competing drug (“these data should not see the light of day,” cautioned an internal e-mail message). And Glaxo made Avandia look good in a major clinical trial by failing to include in its tally of adverse events at least a dozen patients who suffered serious heart problems. The company found reasons to drop them from the study or misreport their ailments.

The company must be watched like a hawk as additional trials that it sponsors go forward.