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Drug Safety
Latest advice for medicines usersThe monthly newsletter from the Medicines and Healthcare products Regulatory Agencyand its independent advisor the Commission on Human Medicines Volume 3, Issue 10 May 2010
Contents
Drug safety advice
Stop press
Other information
from the MHRA
Professionals who prescribe antidepressants will wish to be aware of our The Medicines and
Healthcare products
information this month regarding data from epidemiological studies which suggest Regulatory Agency is the
an increased risk of persistent pulmonary hypertension in the newborn of mothers receiving SSRIs in pregnancy (particularly later stages, p 2). Although there is no responsible for ensuring thatmedicines and medical evidence for an association between SNRIs and PPHN, a potential risk cannot be ruled out given the related mechanism of action. We also have information on epidemiological data suggesting an increased risk of bone fractures in patients The Commission on Human
Medicines gives independent
advice to ministers about the
Also this month, a review of data for carbapenems, a class of beta-lactam antibiotics, has shown a clinically significant interaction with valproic acid/sodium valproate, which results in significantly reduced valproate plasma concentrations is supported in its work byExpert Advisory Groups that with potential for inadequate seizure control. Concomitant use of carbapenems and valproic acid/sodium valproate is not recommended, and prescribers should consider alternative antibacterial therapy (p 4).
On p 6, we inform you that the simvastatin product information now recommendsthat the 80-mg dose should be considered only in patients with severehypercholesterolaemia and high risk of cardiovascular complications who have notachieved their treatment goals on lower doses, when the benefits are expected tooutweigh the potential risks.
The risk of medication errors with oral tacrolimus remains a source of concern, whichis compounded by the introduction of the first generic oral immediate-releasetacrolimus product. There are currently three different formulations of tacrolimus: theyare not interchangeable and it is not safe to switch between these formulationswithout careful therapeutic monitoring and supervision. Read our advice on p 5 tosupport safer use of oral tacrolimus.
Claire Tilstone, Editor
Drug Safety
Volume 3, Issue 10 May 2010 from MHRA and CHM SSRIs and SNRIs: risk of persistent pulmonary
hypertension in the newborn
Keywords: SSRIs, selective serotonin reuptake inhibitors, SNRIs, serotonin and
noradrenaline reuptake inhibitors, persistent pulmonary hypertension in the newborn, PPHN
Epidemiological data suggest that the use of SSRIs in pregnancy, particularly in thelater stages, may increase the risk of persistent pulmonary hypertension in thenewborn. Healthcare professionals are encouraged to enquire about the use of SSRIsand SNRIs, particularly in women in the later stages of pregnancy. Close observationof neonates exposed to SSRIs or SNRIs for signs of PPHN is recommended after birth Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) are antidepressant medicines. A review of epidemiological data has suggested that the use of SSRIs in pregnancy, particularly in the later stages, may increase the risk of persistent pulmonaryhypertension in the newborn (PPHN). The observed risk was approximately fivecases per 1000 pregnancies whereas the background rate in the generalpopulation is one to two cases of PPHN per 1000 pregnancies. PPHN presents assevere hypoxaemia due to pulmonary artery hypertension. Chambers CD, et al. New Engl J Med A retrospective study by Chambers and colleagues1 reported an increased risk of 2006; 354: 579–87.
PPHN in those exposed after 20 weeks’ gestation (odds ratio 6·1 [95% CI2·2–16·8]), but no increased risk of PPHN in fetuses exposed to SSRIs before 20 weeks’ gestation.
A recent epidemiological study conducted by Kallen and Olausson2 aimed to verify the observation of an association between maternal use of SSRIs and PPHN 17: 801–06.
using exposure information recorded before the pregnancy outcome was known.
The study was based on the Swedish medical birth register covering 1997–2005:infants born to women who had used an SSRI during pregnancy during thisperiod were compared with all other infants recorded in the birth register for thoseyears (n=831 324).
After adjustment, an association between maternal SSRI use and PPHN in birthsafter 34 weeks of gestation carried a risk ratio of 2·4 (95% CI 1·2–4·3) based onwomen who reported SSRI use in early pregnancy. From a subgroup who alsohad prescriptions for an SSRI from antenatal care later in pregnancy, the riskestimate was 3·6 (1·2–8·3).2 Although there is no evidence for the association of PPHN to SNRI treatment, this potential risk cannot be ruled out taking into account the relatedmechanisms of action.
Advice for healthcare professionals:
• Healthcare professionals, including midwives, should be aware of the increased risk of PPHN associated with all SSRIs and potentially withSNRIs. The observed increase in risk is about an extra 3–4 cases of PPHNper 1000 pregnancies • In light of these new data, healthcare professionals are encouraged to enquire about the use of these medicines, particularly in women in the laterstages of pregnancy • Close observation of neonates exposed to SSRIs or SNRIs for signs of Drug Safety
Volume 3, Issue 10 May 2010 from MHRA and CHM Antidepressants: risk of fractures
Keywords: antidepressant, fractures, SSRIs, selective serotonin reuptake inhibitors, TCAs,
tricyclic antidepressants
Healthcare professionals should be aware of epidemiological data showing a smallincreased risk of fractures associated with the use of TCAs and SSRIs, and should takethis risk into account in their discussions with patients and in prescribing decisions A review of epidemiological studies, mainly in patients age 50 years or older, shows an increased risk of bone fractures in patients receiving SSRIs (selective serotonin reuptake inhibitors) and TCAs (tricyclic antidepressants). The mechanism leading to this increased risk is unclear. Liu B, et al. Lancet 1998; 351:
Nine reviewed observational studies1–9 give a range of odds ratios for fractures associated with current use of SSRIs (irrespective of dose or duration of use) between 1·4 (95% CI 0·93–2·24) and 2·4 (2·0–2·7). These risks were significant in 2003; 158: 77–84.
French DD, et al. Drugs Aging 2005; most studies. The odds ratios for studies that included TCAs varied between 22: 877–85.
1·2 (0·7–2·2) and 2·2 (1·8–2·8), and in all but one study were lower than the Vestergaard P, et al. Calcif Tissue Int 2008; 82: 92–101.
Six of the nine studies assessed dose response and observed a trend more Psychopharmacol 2008; 28: 384–90.
consistently for SSRIs compared with TCAs. Six of the nine studies assessed Ensrud KE, et al. Arch Intern Med
2003; 163: 949–57.
duration of use and found that the risk of fracture associated with SSRIs seems to Richards JB, et al. Arch Intern Med increase initially to a peak within the first 6–12 months; risk subsequently 2007; 167: 188–94.
decreases, but remains elevated with prolonged use (>1·5 years). Risk with TCAs peaks shortly after initiation (1–2 months) and disappears after prolonged use Psychopharmacol 2008; 28: 411–17.
(>6–12 months). The persistence of the effect after cessation of use was van den Brand MW, et al. Osteoporos
Int 2009; 20: 1705–13.
assessed in four of the nine studies. The increased risk observed for SSRIs and 10 Haney EM, et al. Bone 2009.
TCAs disappears relatively shortly after discontinuation (3–12 months). None of Published online Aug 5, 2009.
doi.org/10.1016/j.bone.2009.07.083. the studies investigated the effects of dose and duration simultaneously.
11 Yadav YK, et al. Cell 2008; 135:
Risk of falls
12 Kerse N, et al. PloS One 2008; 3:
The relationship between SSRIs and fall risk is not clear.10 Several studies show 13 Sterke CS, et al. Int Psychogeriatr that SSRI use is associated with an increased fall risk, and that this risk is higher 2008; 20: 890–910.
than for other types of antidepressants, including mainly TCAs.3,7,11–14 However, 14 Hartikainen S, et al. J Gerontol Med other studies show that SSRIs confer equivalent or lower fall risk to TCAs.6,15 An Sci 2007; 62A: 1172–81.
Italian study of patients receiving home care showed no increased risk of falls with 15 Thapa PB, et al. N Engl J Med 1998; 339: 875–82.
16 Landi F, et al. J Gerontol A Biol Sci Med Sci 2005; 60: 622–26.
SSRIs and decreased bone mineral density
Pscyhopharmacol 2008; 23: 84–87.
Some studies17–20 have found an association between antidepressant use and 18 Mezuk B, et al. J Gerontol A Biol Sci decreased bone mineral density; however, other studies have found no such Med Sci 2008; 63: 1410–15.
19 Haney EM, et al. Arch Intern Med 2007; 167: 1246–51.
Conclusions of the review
20 Diem SJ, et al. Arch Intern Med 2007; 167: 1240–45.
Taking into account the strengths and limitations of the available evidence, 21 Kinjo M, et al. Am J Med 2005; 118:
the review concluded that product information should be updated with a statement on epidemiological findings of an increased risk of bone fractures 22 Spangler L, et al. J Gen Intern Med 2008; 23: 567–74.
From the available data, no definite conclusions could be drawn regarding adose-response relation, time relation, or the underlying mechanism.
Drug Safety
Volume 3, Issue 10 May 2010 from MHRA and CHM Advice for healthcare professionals:
• A review of epidemiological studies, mainly in patients age 50 years or older, shows an increased risk of bone fractures in patients receiving SSRIsand TCAs. The mechanism leading to this increased risk is unclear • Healthcare professionals should be aware of a small increased risk of fractures associated with the use of TCAs and SSRIs, and should take this risk into account in their discussions with patients and in prescribing decisions Carbapenems: concomitant use with valproic acid
not recommended
Keywords: valproic acid, sodium valproate, carbapenems, doripenem, ertapenem,
imipenem-cilastatin, meropenem, antibacterials, anticonvulsant, seizure
A clinically significant interaction between carbapenems and valproic acid results inreduced valproate plasma concentrations with potential for inadequate seizurecontrol. Concomitant use of these agents is not recommended, and healthcareprofessionals should consider alternative antibacterial therapy Carbapenems are a class of beta-lactam antibiotics with broad-spectrumantibacterial activity. They are indicated for the treatment of the following infectionswhen caused by susceptible bacteria: nosocomial pneumonia; complicated intra-abdominal infections; and complicated urinary tract infections. Valproicacid/sodium valproate is an anticonvulsant used for the treatment of generalised,partial, or other epilepsy.
Four carbapenems are authorised in the UK: doripenem (Doribax▼); ertapenem
(Invanz▼); imipenem-cilastatin (Primaxin); and meropenem (Meronem).
Summaries of Product Characteristics are available at
http://emc.medicines.org.uk/.
An interaction between carbapenems and valproic acid has been described in a number of case reports and one identified study.1 The mechanism of the 2007; 41: 1130–36.
interaction has not been elucidated; however, several potential mechanisms have Mori H, et al. Drug Metab Rev 2007; 39: 647–57.
A more-recent unpublished pharmacokinetic study of 24 healthy humanvolunteers found that concomitant administration of valproic acid and doripenemresulted in a rapid and substantial fall in plasma valproate levels. Given the largemagnitude and rapid time course of this interaction, monitoring of sodiumvalproate levels or making dose adjustments are unlikely to manage thisinteraction, which could lead to inadequate seizure control.
A Europe-wide class review of data for the remaining carbapenems found thatdecreased valproic acid levels have also been reported when co-administered withother carbapenems, with 60–100% decreases in valproic acid levels being observed within about 2 days. This interaction is therefore likely to be a class effect.
report from the EU PharmacovigilanceWorking Party at Concomitant use of carbapenems and valproic acid/sodium valproate is not recommended, and prescribers should consider alternative antibacterial therapy. Drug Safety
Volume 3, Issue 10 May 2010 from MHRA and CHM Advice for healthcare professionals:
• A clinically significant interaction between carbapenems and valproic acid/sodium valproate results in reduced valproate plasma concentrationswith potential for inadequate seizure control • Given the large magnitude and rapid time course of this interaction, monitoring of sodium valproate levels or making dose adjustments areunlikely to manage this interaction • Concomitant use of carbapenems in patients taking valproic acid/sodium valproate is not recommended, and prescribers should consider alternativeantibacterial therapy Oral tacrolimus products: measures to reduce risk
of medication errors
Keywords: tacrolimus, Modigraf, Prograf, Advagraf, Adoport
There are three different formulations of tacrolimus; they are not interchangeable. To minimise medication errors arising from different formulations of tacrolimus,prescribers should either: provide full information, stating on the prescription thedrug, the exact pharmaceutical form (capsules or granules; immediate-release orprolonged-release), the strength, and the posology (dose and dose frequency); orprescribe by brand name and include the strength and posology (dose and dosefrequency). Patients should take note of the name of their tacrolimus medicine andthe dose that has been prescribed for them Medication errors
Tacrolimus is an immunosuppressant with a narrow therapeutic index, which maybe given orally to prevent or treat organ transplant rejection. Since 2008, the MHRA has become aware of medication errors due to theunintended switching of different formulations of the original branded oraltacrolimus products in patients who have been treated with tacrolimus for theprevention of organ transplant rejection. Graft rejection reactions and tacrolimustoxicity have resulted from a small number of these medication errors. By the end of February 2010, the MHRA had received 12 case reports involvingprescribing/dispensing errors in association with oral tacrolimus. These included:four cases of acute rejection reaction; three cases of increased drug levels; andtwo cases of increased creatinine.
In January 2009 we published advice in Drug Safety Update on the need for close supervision and monitoring of any change to the prescribed tacrolimus product ordose regimen. We also advised that great care was needed when prescribing anddispensing oral tacrolimus to ensure that the patient receives the intendedformulation and the correct dose. The risk of medication errors remains a sourceof concern, which is compounded by the launch of a novel formulation containingtacrolimus (Modigraf granules for oral suspension) and the introduction, takingplace currently, of the first generic oral immediate-release tacrolimus product(Adoport capsules). Other generics are likely to follow.
Drug Safety
Important: There are three different formulations of tacrolimus; it is
not safe to switch between these formulations:
• Prograf and Adoport are immediate release capsule formulations taken
twice daily. Generic immediate-release tacrolimus capsules are
bioequivalent with Prograf and may be interchanged
• Advagraf is a prolonged release capsule formulation taken once daily
• Modigraf is a granule formulation taken twice daily but is not
These three formulations are not interchangeable; switching between the differentformulations of oral tacrolimus requires careful therapeutic monitoring, and theclose supervision of a transplant specialist. Unsupervised switching can lead tounderdosing or overdosing of tacrolimus, and risks transplant rejection or adversereactions.
Prescribing oral tacrolimus products
In order to minimise the risk of future medication errors and unintended switchingbetween the different formulations, the Commission on Human Medicines and theMHRA recommend that prescribers should either: provide full information, statingon the prescription the drug, the exact pharmaceutical form (capsules orgranules; immediate-release or prolonged-release), the strength, and theposology (dose and dose frequency); or prescribe by brand name and includethe strength and posology (dose and dose frequency). To aid prescribers allgeneric oral tacrolimus products will be approved with a brand name.
Example of prescribing information for oral tacrolimus Prescribing information for an oral tacrolimus medicine should be written asfollows: “Tacrolimus 1 mg prolonged-release capsules. One to be taken once daily” “Advagraf 1 mg. One to be taken once daily” If the exact pharmaceutical form and strength or brand and strength of tacrolimusis not clearly stated on the prescription, the dispensing pharmacist should checkwith the prescriber to ensure that the appropriate medicine is dispensed. Patients should be advised to take careful note of the name of the tacrolimusmedicine and the dose that they are taking, and should check with their doctor orpharmacist if they receive an unfamiliar medicine or if they have questions aboutthe dose.
Changing oral tacrolimus products
This recommendation must not be taken to imply that a patient’s treatment maynot be changed to an alternative tacrolimus product or formulation. However,changes between different formulations, and changes in dosing regimen, shouldalways be accompanied by careful therapeutic monitoring under the supervisionof a transplant specialist.
Drug Safety
Volume 3, Issue 10 May 2010 from MHRA and CHM Advice for healthcare professionals:
• To minimise medication errors arising from different formulations of tacrolimus, prescribers should either: provide full information, stating on theprescription the drug, the exact pharmaceutical form (capsules or granules;immediate-release or prolonged-release), the strength, and the posology(dose and dose frequency); or prescribe by brand name and include thestrength and the posology (dose and dose frequency) • Pharmacists should always dispense the exact pharmaceutical form and strength or brand and strength of oral tacrolimus that has been prescribed,and should contact the prescriber if the prescriber’s intention is not clear, toensure that the appropriate medicine is dispensed • Switching between tacrolimus formulations requires careful medical • Patients should be advised to take careful note of the name of their tacrolimus medicine and the dose that they are taking, and should checkwith their doctor or pharmacist if they receive an unfamiliar medicine or ifthey have questions about the dose Simvastatin: increased risk of myopathy at
high dose (80 mg)
Keywords: simvastatin, Zocor, Inegy, myopathy, statins, lipids, cardiovascular disease
There is an increased risk of myopathy associated with high-dose (80 mg)simvastatin. The 80-mg dose should be considered only in patients with severehypercholesterolaemia and high risk of cardiovascular complications who have notachieved their treatment goals on lower doses, when the benefits are expected tooutweigh the potential risks The simvastatin (Zocor) product information (Summary of Product Characteristicsand Patient Information Leaflet) has been updated to include warnings aboutincreased risk of myopathy in patients receiving the highest licensed dose (80 mg). Similar changes are being implemented to the product information forcombination products that contain simvastatin, such as Inegy (simvastatincombined with ezetimibe).
SEARCH data
This update follows a review of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). SEARCH was a Am Heart J 2007; 154: 815–23.e6.
multicentre, double-blind, active-treatment, factorial-design study conducted at 88sites in the UK, which evaluated the effect of treatment with Zocor 80 mg versus20 mg on major vascular events (MVEs, defined as fatal coronary events, non-fatal myocardial infarction, coronary revascularisation procedure, non-fatal or fatalstroke, or peripheral revascularisation procedure) in 12 064 patients with a historyof myocardial infarction, over a median follow-up of 6·7 years. The results showed that treatment with simvastatin 80 mg did not provide anysignificant benefits over simvastatin 20 mg. The incidence of MVEs was similar for80 mg (1477, 24·5%) versus 20 mg (1553, 25·7%; risk ratio 0·94 [95% CI0·88–1·01]). There was no evidence of increased total or cause-specific Drug Safety
Volume 3, Issue 10 May 2010 from MHRA and CHM mortality, vascular mortality, non-vascular mortality, or higher risk of cancer orhaemorrhagic stroke with the high dose of simvastatin. However, myopathyoccurred in 52 patients (0·9%) randomly assigned simvastatin 80 mg compared with one patient (0·02%) randomly assigned simvastatin 20 mg. An estimated 11 patients in the simvastatin 80-mg group developed rhabdomyolysis compared confirm 100% diagnosis according tothe criteria used.
with none in the simvastatin 20-mg group.
Myopathy
Myopathy is a known side effect of all statins, including simvastatin, and the riskincreases with higher doses. However, its most serious form, rhabdomyolysis is a very rare side effect. The risk of myopathy is greater in: elderly patients (>65 years); women; patients with renal impairment or hypothyroidism; patientswho consume large quantities of alcohol; those with a history of previous muscleproblems during treatment with statins or other lipid-lowering drugs; or those withfamily history of muscle disorders. Concomitant use of some medicines may alsoincrease the risk of muscle damage.
Advice for healthcare professionals:
• Simvastatin 80 mg should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications whohave not achieved their treatment goals on lower doses, when the benefitsare expected to outweigh the potential risks • Prescribers treating patients who are taking simvastatin 80 mg or who are being considered for an up-titration to that dose may need to review theirtreatment during their next visit, to take into account the new evidence • Patients who are currently taking simvastatin 80 mg should not stop taking their medicine. However, they should be advised to contact their doctorimmediately if they experience unexplained muscle pain, tenderness, orweakness • Please report suspected adverse reactions with medicines, including statins, to us via the Yellow Card Scheme (www.yellowcard.gov.uk) Stop press
Panitumumab (Vectibix): serious hypersensitivity
reactions
Panitumumab (Vectibix) is indicated as monotherapy for the treatment of
patients with EGFR (epidermal growth factor receptor)-expressing metastatic
colorectal carcinoma with non-mutated (wild type) KRAS after failure of
chemotherapy regimens.
There have been new reports of serious hypersensitivity reactions (includinganaphylaxis) in patients receiving panitumumab, some of which were fatal. A clinical trial report has been received of a fatal case of angioedema occurring 2 days after exposure following a prior episode of angioedema which occurred 6 days after exposure. Recently, two case reports of fatal hypersensitivity reactionsduring and immediately following panitumumab infusion have been received;these patients had previously experienced hypersensitivity reactions to cetuximaband oxaliplatin, respectively.
Drug Safety
Volume 3, Issue 10 May 2010 from MHRA and CHM Product information has been updated to highlight the following: Advice for healthcare professionals:
• Panitumumab is contraindicated in patients with a history of severe or life-threatening hypersensitivity reactions to this medicine • Serious infusion-related reactions are unpredictable and can occur suddenly. Panitumumab should be permanently discontinued if a severe or life-threatening reaction occurs • In patients with a mild or moderate infusion-related reaction, the infusion rate should be reduced for the duration of the infusion; it is recommendedto maintain this lower infusion rate in all subsequent infusions • Hypersensitivity reactions occurring more than 24 hours after infusion have also been reported. Patients should be warned of a possible late-onset reaction and instructed to contact their physician if symptoms of A letter has been sent to relevant healthcare professionals to inform of these risks.
Other information from the MHRA
PIL of the month: Durogesic D Trans Transdermal
Patch
Patient information leaflets (PILs) are improving in quality as a result of new legal obligations on manufacturers to test the documents with potential patients. Testing makes sure that the presentation of the information enables patients to find and understand key messages for supporting safer use of the medicine within the PILand thereby enables them to use the medicine safely and effectively. To promote this new initiative, we are publishing a series of examples of best practice on our use of fentanyl patches, see DrugSafety Update September 2008, p 2; website. The latest example in the series is the leaflet for Durogesic D Trans
Transdermal Patch, which contains fentanyl—a potent opioid analgesic used
in the management of chronic intractable pain. The leaflet has recently been
redesigned to clarify the posology for these patches and uses good navigation
tools. In testing the leaflet was well received by patients.
Read more about the Commission on Human Medicines, including summaries of Sign up to receive an email alert when a new issue is published: [email protected]

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