Safety of Benzyl Alcohol in Children

• Many product contains benzyl alcohol as a preservative.
• The preservative benzyl alcohol has been associated with serious adverse events, including the “gasping syndrome”, and death in pediatric patients.
• A number of neonatal deaths and severe respiratory and metabolic complications in low-birth-weight premature infants have been associated with use of this agent in bacteriostatic saline intravascular flush and endotracheal tube lavage solutions

Reference Levels

• a subchronic oral reference dose of 1 mg/kg/day for adult was derived based on the no observed adverse effect level of 200 mg/kg found in a 13 weeks rat study.
• A chronic oral reference dose of 0.3 mg/kg/day for adult was derived based on the LOAEL of 200 mg/kg found in a 2 years carcinogenicity study
• no animal toxicological data for parenteral or topical use of benzyl alcohol. However, oral absorption is close to 100%, hence recommendations for oral use are considered applicable for other routes of administration
• oral juvenile studies, only one short-term study has been performed in juvenile rats, which established a NOAEL of 300 mg/kg/day which is close to the adult. There are no juvenile animal toxicity studies related to long-term use.
• Benzyl alcohol can cross the placenta

Benzyl Alcohol Toxicity (“Gasping Syndrome”)

• Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known.
• The risk of benzyl alcohol toxicity depends on the quantity administered and the hepatic capacity to detoxify the chemical.
• Premature and low birth weight infants may be more likely to develop toxicity.

Metabolic Acidosis (commonly associated with NS alcohol flush)

• Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid.
• However, this metabolic pathway may not be well developed in premature infants.
• The benzyl alcohol may therefore have been metabolized to benzoic acid, which could not be conjugated by the immature liver but accumulated, causing metabolic acidosis

Usage in Pediatrics

• current recommendations are incomplete and too strict, as they contra-indicate benzyl alcohol for children up to 3 years old (European Medicines Agency).
• While this excipient should not be used in neonates, it may be used for children aged older than 4 weeks with caution(European Medicines Agency).
• Retrospective studies have now demonstrated a significant decline in mortality and other adverse events after discontinuation of use of a benzyl alcohol-containing solution to flush intravascular catheters or reconstitution of drugs for delivery through these catheters in the newborn population
• No specific cut off points is available for Benzyl alcohol administered intravenously, however  in the range of 100 to 200 mg/kg/day has been linked to the “gasping syndrome” in several pre-term newborns with metabolic acidosis that resulted in deterioration of the neurological status, cardio-vascular failure and haematological anomalies .
• Premature infants receiving low doses in medications were found to have peak benzoic acid levels 10 times higher than those in term infants but without evidence of toxicity.
• Two studies noting the striking decrease in kernicterus after removal of benzyl alcohol did not reveal a dose–response relationship and could not exclude the possibility that other advances in therapy were responsible

Recommendations

• At low doses, such as those present when medications preserved with benzyl alcohol are administered, benzyl alcohol is safe for newborns
• Content of benzyl alcohol as preservatives in IV medications are generally at lower levels than given safety levels (consult pharmacists for individual agents)
• Avoid in Premature, low birth weight babies and liver impairment

References:

1. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm403291.htm
2. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm
3. Questions and Answers on Benzyl alcohol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00). European Medicines Agency, 2014 (Draft)
4. http://pediatrics.aappublications.org/content/99/2/268

Progestogen for Threatened Miscarriage

• Threatened miscarriage is when a mother might be losing her baby at less than 20 weeks' gestation.
• The signs are vaginal bleeding, with or without abdominal pain, while the cervix is closed.
• The use of ultrasound scans in the management of bleeding in early pregnancy has improved the diagnosis and management, as attempts to maintain a pregnancy are likely to be effective only if the fetus is viable and has no chromosomal abnormalities.
• Once the cervix begins to open, pregnancy loss is inevitable.
• Women who continue with their pregnancy after threatened miscarriage were found to have increased risk of antepartum haemorrhage, pre-labour rupture of the membranes, preterm delivery, and intrauterine growth restriction.

Rationale for progestogen

• Progestogen is an essential hormone both for establishing and maintaining pregnancy
• It has been postulated that some miscarriages are due to corpus luteum deficiency/luteal phase defect (LPD) where the corpus luteum produces a suboptimal amount of progesterone, resulting in retarded endometrial development
• Exogenous progesterone supplementation can occur in various forms such as medroxyprogesterone acetate, 17-alpha-hydroxyprogesterone caproate, progesterone and dydrogesterone
• Various meta-analyses have also been done to study the effects of progestational agents in miscarriage prevention in the general population, with conflicting results

Evidence for Use

• The review of trials located four randomised studies involving 421 women that compared the use of progestogens in the treatment of threatened miscarriage with either placebo or no treatment.
• The limited evidence suggests that the use of a progestogen does reduce the rate of spontaneous miscarriage.
• Two trials reported that treatment with progestogens did not increase the occurrence of congenital abnormalities in the newborns and the women did not have any significant difference in incidence of pregnancy-induced hypertension nor antepartum haemorrhage
• Progestogen therapy was not associated with any adverse effects on the woman. Although slightly more fetal/neonatal adverse events (fetal abnormalities and neonatal deaths) were identified among women receiving progestogen, the numbers were far too small − partly because of the rarity of such events − to qualify as a potential risk.

Evidence against use

• There was no evidence of effectiveness of vaginally given progesterone in reducing the risk of miscarriage for women with threatened miscarriage
• Progestogens do not prevent miscarriage in early-to-mid pregnancy.
• Results from the four small trials showing a positive effect of progestogens in the subgroup of women with recurrent miscarriage should be interpreted with caution because of the small number of subjects in those trials and the wide confidence interval
• no evidence for an effect favouring the use of progestagens in women with recurrent miscarriage was found when compared to placebo

Medroxyprogesterone

• FDA has considered it to be a category X drug, which means that it is contraindicated in women who are or may become pregnant.
• The older studies also show no reduction in miscarriage rates with medroxyprogesterone.

17-hydroxyprogesterone caproate

• A review revealed that there was no effect in miscarriage prevention, even in patients who had previously suffered from recurrent miscarriages
• considered a category D drug by the FDA,which means that there is positive evidence of human foetal risk,
• While its use in early trimester for the prevention of miscarriage is contraindicated, its use in pregnancy has been resurrected by recent evidence that it reduces the preterm labour rates in those patients at high risk of preterm labour when administered weekly from 16 gestational weeks onwards.

Dydrogesterone

• A small recent RCT on its use in the context of a threatened miscarriage showed that there was an improvement in outcome with more continuing pregnancies in the treatment group
• no reports of foetal abnormalities other than an isolated incident of a non-virilising abnormality of the genitourinary tract, when dydrogesterone was used together with hydroxyprogesterone caproate.

Recommendations

• based on scarce data there is no evidence to support the routine use of progestagens for the treatment of threatened miscarriage.
• information about potential harms to the mother or child, or both, with the use of progestagens is lacking.
• there has been much speculation about progestagens but the results of these meta-analysis show no statistically significant difference between women receiving progestagens for preventing threatened miscarriage or miscarriage when compared to placebo,

References:

1. Progestogen for preventing miscarriage : RHL commentary (last revised: 2 February 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.
2. Progestogen for treating threatened miscarriage. http://www.cochrane.org/CD005943/PREG_progestogen-for-treating-threatened-miscarriage
3. Non-surgical interventions for threatened and recurrent miscarriages. Singapore Med J 2007; 48(12):1074–1090
4. Use of progestagens during early pregnancy. FVV in ObGyn, 2013, 5 (1): 66-71

Seizures in Hepatic Encephalopathy

• Seizures have traditionally been viewed as a rare event in hepatic encephalopathy
• Overall incidence of seizures in hepatic encephalopathy varies between 2% and 33%
• Seizure activity has been reported in previous clinical series of acute liver failure and is a well-recognized complication of acute hyperammonemia in urea-cycle disorders
• Non-convulsive status epilepticus may be particularly common in these patients

Treatment

• Absolute data for safety profile of drugs in liver disease is still not clear, as changes of pharmacokinetics make choice of drugs difficult.
• Free drug concentrations may be higher, making plasma concentration monitoring essential in such circumstances.
• A single seizure may not require therapy. However when started, antiepileptic drugs are usually discontinued early.
• Drugs with sedative effects are best avoided because of a risk of precipitating coma.
• Phenytoin and gabapentin are relatively preferred drugs; however, monitoring of drug levels is desirable.

Evidences

• the use of phenytoin was shown to significantly reduced seizure frequency and the development of increased ICP
• In a recent controlled trial, subclinical seizure activity was detected in 10 of 22 patients enrolled as controls in a trial of prophylactic phenytoin in ALF. At autopsy, patients in the nontreated group had greater evidence of cerebral edema

Safety of Phenytoin

• Is highly protein bound (90%), primarily binding to albumin
• Elimination occurs chiefly through hepatic microsomal biotransformation
• In hepatic insufficiency, presence of low albumin/reduced binding capacity may lead to higher drug levels and potential toxicity
• Nonlinear kinetics and difficulty in estimating hepatic metabolic capacity limits the ability to predict dose adjustment

Management of agitation

• includes physical restraint and medication.
• Benzodiazepines are best avoided.
• Haloperidol is a safer choice in the presence of liver disease

References:

1. http://www.medscape.com/viewarticle/463473_2
2. http://www.ncbi.nlm.nih.gov/pubmed/15025257
3. http://www.ncbi.nlm.nih.gov/pubmed/17190918
4. http://www.hindawi.com/journals/ijh/2011/841407/
5. Management of agitation and convulsions in hepatic encephalopathy. Indian society of Gastroenterology
6. Hepatic encephalopathy with status epileptics: A case report. World J Gastroenterol 2006 March 21; 12(11): 1793-1794

Etoricoxib : Safety Update

FDA

• etoricoxib, or Arcoxia, is still not FDA approved in the United States.
• Concerns about the similar structure and mechanism to rofecoxib, or Vioxx, has the FDA wary about approval for etoricoxib. Vioxx was pulled from the market in 2004 due to many adverse reports of cardiovascular complications, specifically stroke and heart attack.
• In April 2007 the FDA officially rejected the application for a U.S. approval for Arcoxia.
• Besides a potential for negative cardiovascular effects, other side effects for etoricoxib include nausea, stomach pain, edema in the hands and feet, bruising and dyspepsia.
• Despite the lack of FDA approval, many countries find success in patients using etoricoxib

MHRA

• has concluded that etoricoxib’s benefits outweigh the risks in the treatment of rheumatoid arthritis.
• Furthermore, the Committee recommended extension of the indication to include ankylosing spondylitis at a dose of 90 mg once a day.
• Committee recommended an update to the existing contraindication in patients with inadequately controlled hypertension to state that patients whose blood pressure is persistently above 140/90 mmHg and inadequately controlled must not receive etoricoxib.
• Furthermore, high blood pressure should be controlled before starting treatment, and should be monitored for 2 weeks after the start of treatment and regularly thereafter.

NPS Australia

• In July 2008 the Pharmaceutical Benefits Advisory Committee rejected an application to list etoricoxib on the PBS for osteoarthritis, concluding that there was no demonstrated need to list another COX-2 selective NSAID and that etoricoxib appears to cause more episodes of hypertension than celecoxib.
• In most other respects the efficacy and safety of etoricoxib are similar to those of celecoxib. In 2 trials comparing celecoxib 200 mg once daily with etoricoxib 30 mg once daily in people with osteoarthritis, over 26 weeks etoricoxib was no worse than celecoxib at reducing pain and improving function.
•  The 2 drugs are likely to have similar gastrointestinal safety, although only imprecise estimates of the comparative rates of serious gastrointestinal injury (e.g. perforations, obstructions and bleeding) are available

Malaysia / Recommendation

• Based on our regulatory board, Etoricoxib is still indicated and beneficial in treatment (benefit outweighs harm)
• However, prescribing should be carried out based on the Indication and Contraindication and the shortest period as possible.\
• based on a meta analysis, treatment with etoricoxib proved not to result in an increased risk of serious vascular events when compared with both the placebo and naproxen. 

INDICATIONS

• Acute and chronic treatment of the signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA)
• The management of ankylosing spondylitis (AS)
• Treatment of acute gouty arthritis
• Relief of acute pain, including pain related to minor dental procedures
• Relief of chronic musculoskeletal pain
• The decision to prescribe a selective COX-2 inhibitor should only be made:
•  if non-pharmacological interventions and simple analgesic therapy i.e paracetamol have been tried and found to lack analgesic efficacy or to have unacceptable adverse effects in the individual patient; and
• after assessment of the individual patient's overall risk factors for developing severe
• adverse events e.g. history of cardiovascular, renal, or gastrointestinal disease

Contraindication

• Hypersensitivity to the active substance or to any of the excipients
• Active peptic ulceration or active gastro-intestinal (GI) bleeding.
• Patients who, after taking acetylsalicylic or NSAIDs including COX-2 (cyclooxygenase-2) inhibitors, experience bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria, or allergic-type reactions.
• Pregnancy and lactation
• Severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥10).
• Estimated renal creatinine clearance <30 ml/min.
• Children and adolescents under 16 years of age.
• Inflammatory bowel disease.
• Congestive heart failure (NYHA II-IV).
• Patients with hypertension whose blood pressure is persistently elevated above 140/90mmHg and has not been adequately controlled.
• Established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease

References

1. http://www.nps.org.au/publications/health-professional/nps-radar/2009/december-2009/brief-item-etoricoxib
2. https://www.gov.uk/drug-safety-update/etoricoxib-prescribing-to-patients-with-high-blood-pressure
3. http://www.australianprescriber.com/magazine/32/5/142/5/drug/894/etoricoxib
4. Arcoxia, NEW ZEALAND DATA SHEET.
5. ADR Newsletter May 2007.
6. https://www.medicines.org.uk/emc/medicine/29136 
7. http://www.minervamedica.it/en/journals/minerva-cardioangiologica/article.php?cod=R05Y2014N06A0437