Unlicensed Drug Research Articles

Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety

This review aims to give an updated overview of the worldwide situation of off-label and unlicensed drug use in the paediatric field, also taking into account the safety of this kind of treatment. A Medline and Embase search was performed between 1990 and 2006 and a total of 52 studies were identified and included in the systematic review. From the authors’ analysis of the literature, the extent of paediatric unlicensed/off label use is higher in neonatal and paediatric intensive care units and oncology wards, compared with primary care. Moreover, among the nine studies reporting the contribution of an off-label/unlicensed drug use to the occurrence of adverse events, the percentage of unlicensed and/or off-label prescriptions involved in an adverse drug reaction ranged between 23 and 60%. To ensure that children are not exposed to unnecessary risks, controlled clinical trials are required. In addition, future research should be directed towards the identification of individual drugs that cause serious adverse drug reactions and lack product information.

Supporting the changes in nurse prescribing

On 1 May 2006, the Nurse Prescribers’ Extended Formulary ceased to exist. All extended formulary nurse prescribers were automatically registered as independent prescribers by the NMC. Independent prescribers are able to prescribe from the entire British National Formulary (BNF), within their scope of practice, with the exception of unlicensed drugs and most controlled drugs. This exciting step is not without risk. A strong clinical governance framework is essential to manage a safe and effective transition (Royal Pharmaceutical Society of Great Britain, 2006).

Use of unlicensed drugs: what are the issues?

Use of unlicensed drugs: what are the issues?

Pain and Use of Complementary and Alternative Medicine in a National Sample of Persons Living with HIV

The current study investigated the relationship of pain to use of complementary and alternative medicine (CAM) in a U.S. nationally representative sample of 2466 persons with human immunodeficiency virus (HIV), using data from the HIV Cost and Services Utilization Study. Pain was conceptualized as a need characteristic within the context of predisposing, enabling, and need (PEN) characteristics following Andersen's Behavioral Model of Health Services Use. Multivariate analyses were used to examine the association of baseline PEN characteristics with CAM use by follow-up (approximately 6 months later), including use of five specific CAM domains. Change in pain from baseline to follow-up was also examined in relation to CAM use. Baseline pain was a strong predictor of CAM use, and increased pain over time was associated with use of unlicensed or underground drugs with potential for harm. These results highlight the importance of medical efforts to control pain in persons living with HIV.

Salvage Therapy for Aspergillosis

Participants at the John E. Bennett Forum on Design of Clinical Trials for Fungal Infections suggested guidelines for the regulatory approval of drugs solely on the basis of salvage therapy--that is, the use of an unlicensed drug to treat patients who have experienced failure with or who have been intolerant of an approved drug. The topics covered included requirements for study design (i.e., the design allows the comparison of comparable items), entry criteria (in particular, the duration of therapy before salvage therapy is introduced), and outcome criteria that determine whether or not the treatment was successful.

Off label and unlicensed drugs use in paediatric cardiology

The use of drugs in an off label or unlicensed manner to treat children is a widespread phenomenon in Europe and the United States. The incidence of unlicensed and off label prescribing in paediatric cardiology practice has not been studied to date. This study was designed to assess the extent and nature of off label and unlicensed drug use in paediatric cardiology inpatients. In a prospective study, drug prescriptions in a paediatric cardiology ward were reviewed during a 2-year period. Data were collected and analyzed by special software created for this purpose. The children (n = 544) studied varied in age from 4 h to 18 years. One or more off label and unlicensed prescriptions were given to 414 (76%) patients. Of the 2,130 prescriptions given during the 2-year period, more than one-half were unlicensed (11%) or off label (47%). While children aged 2-11 years received most of the unlicensed drug prescriptions (17%), neonates, who did not receive unlicensed drugs, led (64%) in the use of off label drugs. CONCLUSIONS. This study showed that the problem of off label and unlicensed drug use also exists in paediatric cardiology. The findings imply that the phenomenon of off label and unlicensed use of drugs in children can be correlated with the deficiency of paediatric drug formulations on the global market and insufficient data from clinical studies which must be performed to confirm the efficacy and safety of drugs in the paediatric population. Therefore, efforts to improve paediatric labelling are important and need the full support of all involved.

Changes in Medical and Nursing Care in Cancer Patients Transferred from a Palliative Care Team to a Palliative Care Unit

The primary aim of this study was to explore the changes in medical/nursing care in patients who transferred from a palliative care team (PCT) to a palliative care unit (PCU) in the same hospital, and to explore the reasons why new or modified interventions were required. This was a retrospective study of 50 consecutive patients who were transferred from PCT to PCU in a 750-bed general hospital. A trained nurse performed a chart review and recorded the changes in 1) medical/nursing care, 2) help with decision-making within 48 hours after PCU admission, and 3) documentation of family and psycho-existential care. Group discussions among PCT and PCU staff members explored the potential reasons for the changes. Five patients were excluded due to admission periods of shorter than 48 hours. The number of new/modified medical and nursing care interventions after PCU admission averaged 1.9 ± 1.5 and 1.5 ± 1.3 per patient, respectively. The most common medical treatments were: reduction in hydration volume, dose titration of opioids, change in opioid administration device, opioid rotation, and addition of NSAIDs and steroids. The most common nursing interventions were: allowing patient to take a bath, changing mattress, use of massage, and discontinuation of bronchial suctioning. In addition, PCU staff newly coordinated opportunities to discuss preferred end-of-life care with primary caregivers in 38% of the cases, family members other than primary caregivers in 16%, and patients in 6.7%. The chart documentation of family care and psycho-existential care increased considerably after PCU admission. The chief reasons for these changes were: under-recognition of the problems and unavailability of treatments (pharmacological treatments), no intention to intervene and recommendations not followed by primary physicians (rehydration therapy), no intention to intervene (nursing care), and no intention to intervene and under-recognition of the problems (help with decision-making). These data demonstrate that many patients under PCT consultation receive new or modified interventions after PCU admission. Potentially useful strategies to strengthen the PCT interventions are: modification of intervention structure to minimize under-recognition of symptoms and decision making problems (e.g., use of standardized assessment tools, regular conferences), changes in the health care system to allow unlicensed drugs, clinical studies to clarify the benefits of artificial hydration therapy, and greater efforts to intervene in the areas of nursing care, help with decision making, family care, and psycho-existential care.

A literature review on off-label drug use in children

The aim was to compare results of studies performed in different settings worldwide and identify common therapeutic areas to allow for focused interventions, because off-label drug use can be a measure of the lack of knowledge concerning paediatric treatments. A secondary objective was to provide a brief review of efforts to date. A literature review of articles on off-label and unlicensed drug use in children involving general prescription samples was performed using Medline and Embase. In all, 30 studies from 1985-2004 were included. Eleven involved paediatric hospital wards, seven neonatal hospital wards, and 12 the community setting. The off-label and unlicensed classification methods varied, making results difficult to compare. In general, off-label/unlicensed prescription rates ranged from 11%-80%, and higher rates were found in younger versus older patients and in the hospital versus community settings. On the paediatric hospital wards, off-label/unlicensed prescriptions ranged from 16%-62% and most often concerned acetaminophen, cisapride, chloral hydrate, and salbutamol. In the neonatal wards, rates ranged from 55%-80% and often involved caffeine. In the community setting, rates ranged from 11%-37% and the most commonly implicated drugs were salbutamol and amoxicillin. A lack of harmonization between the evidence, the information available to doctors, and its use in clinical practice exists and this is part of the reason off-label therapies are so common. Attempts have been made to improve knowledge concerning paediatric treatments, but more focused interventions are needed, also taking into consideration this lack of harmonization.

News Round-Up Archive 2004: Unlicensed drugs legislation for SP in 2005? 14/09/04

<i>News Round-Up Archive 2004</i>: Unlicensed drugs legislation for SP in 2005? 14/09/04

The impact of unlicensed and off-label drug use on adverse drug reactions in paediatric patients.

Many drugs that are used to treat children are either not licensed for use in paediatric patients (unlicensed) or prescribed outside the terms of the product licence (off label). The incidence of adverse drug reactions (ADRs) associated with the use of such drugs is yet to be established. This study investigates, for the first time in a German patient population, the impact of unlicensed and off-label drug use on ADRs in paediatric patients. An 8-month prospective pharmacoepidemiological cohort-based survey was conducted on a ten-bed paediatric isolation ward at the University Hospital Erlangen-Nuremberg, Germany. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were characterised according to international classification methods. All drug prescriptions were evaluated retrospectively as to unlicensed or off-label use on the basis of the product information. A total of 178 patients were included in the study and 740 drug prescriptions were given to 156 patients (median three prescriptions per patient). In 198 cases (27.7% of all prescriptions) drugs were used in either an unlicensed (n = 3) or off-label (n = 195) manner. A total of 46 ADRs were observed in 31 patients (17.4%). Patients receiving at least one unlicensed or off-label drug prescription during hospitalisation (n = 92) experienced an ADR significantly more frequently (n = 26 patients) than patients receiving only licensed drugs (n = 64 vs 5 patients). ADRs were associated with 29 (5.6%) of the 517 licensed drug prescriptions and with 12 (6.1%) of the 198 unlicensed or off-label drug prescriptions. The majority of ADRs caused by unlicensed and off-label drug use were recognised by the attending physician. However, statistical analysis revealed no significant difference in the number of licensed and unlicensed/off-label drug prescriptions causing ADRs. This study demonstrated that at a paediatric isolation ward the incidence of ADRs caused by unlicensed or off-label drug use was not significantly more than that caused by the licensed drug use. However, patients treated with unlicensed or off-label drugs were shown to possess a significantly increased risk for developing ADRs.

The drugs we deserve

The drugs we deserve

The drugs we deserve

The drugs we deserve

Risk factors for unlicensed and off-label drug use in children outside the hospital.

To establish risk factors of unlicensed and off-label drug use by children outside the hospital. A cross-sectional study based on 66 222 pharmacy dispensing records for the year 2000 was performed in the northern part of the Netherlands. All prescriptions were divided into the following categories: unlicensed (no product license), off-label (licensed drugs used outside the terms of the product license), and on-label (licensed drugs used according to the product license). For identifying possible problem areas, the proportions of unlicensed and off-label drug use were determined per age group (0-1, 2-5, 6-11, or 12-16 years) and per drug group. For all systemic drugs, a logistic regression was done that models the odds of receiving an unlicensed or off-label prescription as a function of several possible risk factors. Unlicensed drug use in Dutch children is the highest among 0 to 1-year-olds, and off-label drug use is the highest among 12- to 16-year-olds. Drug groups with highest percentages of unlicensed and off-label drug use were ophthalmologicals/otologicals (80.7% of all prescriptions in this group), blood and blood-forming organs (mainly vitamin K for breastfed newborns; 75.7%), cardiovascular drugs (74.7%), and dermatologicals (73.3%). Prescriptions by specialists (outpatient), prescriptions for new drugs, prescriptions for drugs with a low use in the pediatric population, and prescriptions for infants were risk factors for using a systemic drug unlicensed or off-label. Efforts to improve pediatric labeling are important and need full support. The present results can be used to focus these efforts.

Unlicensed and off label drug use in acute lymphoblastic leukaemia and other malignancies in children

The need to use unlicensed and off label drugs in children due to the lack of suitable, licensed formulations with appropriate prescribing information creates many problems on an everyday basis for healthcare professionals, carers and children. This prospective study was designed to examine the incidence and nature of unlicensed and off label prescribing, in paediatric oncology patients with acute lymphoblastic leukaemia and other malignancies. Inpatient and outpatient prescriptions were analysed for a 4-week period. All patients received at least one unlicensed or off label drug. Fifty-five per cent of prescriptions were licensed, 19% were unlicensed and 26% were licensed drugs used in an off label manner. Unlicensed preparations were used in 40% of prescriptions for cytotoxic agents, due to a lack of commercially available formulations suitable for the paediatric patient. These drugs included mercaptopurine and methotrexate which have been used in the treatment of paediatric leukaemia for many years, their efficacy having been demonstrated by on-going Medical Research Council trials. It is disappointing that drugs, which are the mainstay of therapy for paediatric leukaemia and other malignancies, are unavailable in appropriate licensed formulations to facilitate their administration to children. This needs to be urgently addressed.

Unlicensed and off-label drug use in an Australian neonatal intensive care unit.

To determine the extent of unlicensed and off-label drugs prescribed in the level 3 neonatal intensive care unit (NICU) at the Royal Women's Hospital, Melbourne, Australia. A prospective cohort study was conducted of all infants who were admitted to the NICU during a 10-week period. Each drug prescribed was evaluated in relation to the licensed approved uses to determine whether the drug was administered in a licensed manner or was unlicensed or used in an off-label manner. There were a total of 101 admissions involving 97 infants. A total of 1442 prescriptions were administered; 42% were licensed, 11% were unlicensed, and 47% were off-label. Twenty-one percent were off-label for 2 or more reasons. Eighty percent of infants received either an unlicensed or an off-label prescription or both; this proportion rose to 93% of extremely low birth weight infants. This is the largest study performed of unlicensed and off-label drug use in the NICU. This practice remains widespread despite clear recommendations to improve this undesirable situation. The attendant risks to infants and prescribers remain. It is time for legislation to be introduced to govern this area.

Tramadol for pain relief in children undergoing tonsillectomy. A comparison with morphine

Introduction Pain control for paediatric patients undergoing tonsillectomy remains problematic. The combination of intra‐operative morphine and rectal diclofenac results in a high incidence of post‐operative nausea and vomiting as well further analgesic requirements. Tramadol is reported to be an effective analgesic and have a side effect profile similar to morphine. It is not classed as a controlled drug and is available in tablet, suppository and injection form. It is currently not licensed for paediatric use in the UK.Methods We conducted a prospective, double blind, randomised controlled trial in children scheduled for elective tonsillectomy or adenotonsillectomy at the Royal Aberdeen Children Hospital. Following local ethics committee approval and obtaining a drug exemption certificate from the Medicines Licensing Agency for an unlicensed drug in paediatrics we recruited 60 patients into three groups: morphine (0.1 mg·kg−1), tramadol (1 mg·kg−1) and tramadol (2 mg·kg−1). These drugs were given as a single injection following induction of anaesthesia. In addition, all patients received diclofenac (1 mg·kg−1) rectally. The post‐operative analgesic requirements, sedation scores, signs of respiratory depression and nausea and vomiting as well as antiemetic requirements were noted at 4 hourly intervals until discharge. Statistical analysis was performed using chi‐square, Kruskal–Wallis and one‐way anova tests as appropriate. P &lt; 0.05 was considered statistically significant.Results There were no statistical significant differences in age, weight, type of operation or induction of anaesthesia, 4 hourly sedation and pain scores and further analgesic requirements. There were no incidences of respiratory depression. Morphine was associated with a significantly higher incidence of vomiting following discharge to the wards (75% vs 40%, P = 0.03) when compared to both tramadol groups. The differences in anti‐emetic requirements did not reach statistically significant difference (P = 0.078).Conclusions We conclude that tramadol has similar analgesic properties and side effects when compared with morphine. The pharmaceutical presentation and the availability as a non‐controlled substance may make it a useful addition to paediatric anaesthesia if it becomes licensed for paediatric anaesthesia in the UK.

Vital unlicensed and off-label drug use thwarts paediatric rights

Vital unlicensed and off-label drug use thwarts paediatric rights

Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands.

Many drugs used in paediatric care are not licensed for that use or are prescribed outside the terms of the product license (off-label). Studies in the UK and Europe showed a large number of unlicensed and off-label drug prescription in specialised paediatric health care centres. We determined the extent and nature of use of unlicensed drugs and off-label prescriptions in children in a general hospital in the Netherlands. We conducted a longitudinal prospective cohort study in a dynamic population consisting of patients admitted to the paediatric ward and the neonatology unit of a general hospital during a 19-week period. Drug-licensing status of all prescriptions given to these patients was determined. A total of 1017 prescriptions was administered to 293 paediatric patients for 114 different drugs. The median number of prescriptions per patient was three (interquartile range 2-5). The most commonly administered drugs were acetaminophen (14%), cefotaxime (8%), amoxicillin (7%), caffeine (4%) and prednisolone (4%). Four hundred and forty-three (44%) prescriptions were off-label, and 285 (28%) were for unlicensed drugs. Ninety-two percent of patients received one or more unlicensed or off-label prescriptions, and this proportion was significantly higher in children below 6 months of age than in older children. This study shows that the extent of unlicensed and off-label drug prescription in a paediatric ward and neonatology unit of a general hospital is large and not smaller than in an academic paediatric setting. Lack of paediatric drug labelling is therefore not solely a problem with drugs used in university hospitals, but also in general hospitals. Efforts must be taken to change the current situation.

Unlicensed and off-label drug use in children: implications for safety.

A significant number of children receive either an unlicensed or an off-label drug during their stay in hospital. Studies throughout Europe have shown that at least one-third of children in hospital and up to 90% of neonates in a neonatal intensive care unit receive such drug prescriptions. The medicines that are most frequently used off-label include analgesics, antibiotics and bronchodilators. The purpose of licensing a drug is to ensure safety, efficacy and quality. If a drug is used in a different manner, one would expect a greater risk of toxicity. Only three studies have commented on the risk of toxicity in relation to unlicensed or off-label drug use. Only one of these three studies prospectively tried to evaluate the risk associated with off-label and unlicensed drug prescription. This study suggested that the percentage of unlicensed and off-label drug use was significantly associated with the risk of an adverse drug reaction. Two studies looking at adverse drug reactions suggest that there is a greater risk of a severe adverse drug reaction occurring in association with the off-label or unlicensed use of drugs. One study found that five out of eight severe adverse drug reactions were associated with the off-label use of a medicine. The other study found that 14 of 19 drug prescriptions associated with 17 severe adverse drug reactions were either unlicensed or off-label. The risk of prescribing off-label and unlicensed drugs in children is not clear from the limited data available.

Unlicensed drug use on ICU

The use of medicines outside the terms of the product licence is a common occurrence on the ICU. While the extent of unlicensed prescribing has been quantified in paediatric practice [1], no studies have so far addressed this in the adult ICU setting. There are various types of unlicensed drug use including an unlicensed drug or a licensed drug used in an unlicensed manner. Identifying unlicensed drug use is important because the prescriber is responsible for any adverse effects suffered by the patient.