Paroxetine: safety and tolerability issues

Paroxetine is a selective serotonin re-uptake inhibitor (SSRI) available in immediate release and controlled release (CR) formulations. Paroxetine is the most potent inhibitor of serotonin re-uptake among the now available SSRIs. Paroxetine has been approved for the treatment of major depressive disorder (MDD), obsessive–compulsive disorder, panic disorder (PD), generalised anxiety disorder, post traumatic stress disorder (PTSD), and social anxiety disorder (SAD) in adults, whereas paroxetine CR is approved for the treatment of MDD, SAD, PD and premenstrual dysphoric disorder in adults. The overall efficacy of paroxetine seems to be comparable to other SSRIs in the treatment of approved indications, although paroxetine treatment induces more sedation, constipation, sexual dysfunction, discontinuation syndrome and weight gain than other SSRIs. Recent data suggest that paroxetine treatment leads to increased rates of congenital malformations, although this evidence is not conclusive. Paroxetine and paroxetine CR are not indicated for use in the paediatric population and are categorised as Pregnancy Class D. In conclusion, whether the tolerability profile of paroxetine differs substantially from other new antidepressants (including other SSRIs) needs to be determined in adequately powered well-designed randomised controlled comparative clinical trials.     

Octreotide LAR: safety and tolerability issues

Background: Somatostatin analogues are the cornerstone in therapy of acromegaly and functioning neuroendocrine tumors. Long-acting retard formulations have improved patient survival and contributed considerably to quality of life. The first such compound was octreotide LAR (‘long-acting release’), characterized by high affinity to somatostatin receptor subtypes 2 and 5, which has to be injected intramuscularly every 4 weeks. Objective: The aim was to screen all octreotide LAR-related literature and assess the compound's profile for safety and tolerability. Methods: An extensive literature search has been performed using the MEDLINE database to retrieve data from clinical studies evaluating the efficacy and tolerability of octreotide LAR. Results/conclusion: Octreotide LAR is well tolerated; however, diarrhea and gallstone formation were identified as the main adverse events. Impairment of glucose homeostasis was a regular phenomenon, but its occurrence was unpredictable. General side effects such as headache, abdominal discomfort or fatigue were also reported. According to incidental case reports, administration during pregnancy appears to be safe for both mother and child; however, definitive evidence is missing. In addition, octreotide LAR has been evaluated for further indications including treatment of solid tumor entities, due to its antiproliferative effect. Currently, several compounds (lanreotide, SOM230) with a broader receptor spectrum are under evaluation and may improve treatment efficacy and lower incidence of side effects.     

Long-term treatment with infliximab in inflammatory bowel disease: safety and tolerability issues

Crohn's disease and ulcerative colitis represent the most common forms of inflammatory bowel disease (IBD), clinical conditions affecting the small and/or large bowel. It is well known that IBD is an immune-mediated condition and that TNF-alpha plays a pivotal role in the pathogenesis of the disease. TNF-alpha has been scrupulously studied as a target for therapeutic intervention in this setting. A number of biologic compounds have been developed, including the European Medicine Agency (EMEA)-approved agents, infliximab and adalimumab. Although their efficacy in induction and maintenance of remission has been established by several clinical trials, many issues regarding safety remain to be elucidated. In fact, anti-TNF treatment may be associated with a number of rare, but serious, adverse events, including infusion reactions, infections, lymphomas and other malignancies. A black-box warning has to be taken into consideration when looking at potential serious infections such as tuberculosis. Active infections, demyelinating disorders and severe heart failure are contraindications for anti-TNF treatment. This review focuses on drug toxicity and adverse events related to infliximab treatment in IBD.     

Long-term treatment with infliximab in inflammatory bowel disease: safety and tolerability issues

Crohn's disease and ulcerative colitis represent the most common forms of inflammatory bowel disease (IBD), clinical conditions affecting the small and/or large bowel. It is well known that IBD is an immune-mediated condition and that TNF-α plays a pivotal role in the pathogenesis of the disease. TNF-α has been scrupulously studied as a target for therapeutic intervention in this setting. A number of biologic compounds have been developed, including the European Medicine Agency (EMEA)-approved agents, infliximab and adalimumab. Although their efficacy in induction and maintenance of remission has been established by several clinical trials, many issues regarding safety remain to be elucidated. In fact, anti-TNF treatment may be associated with a number of rare, but serious, adverse events, including infusion reactions, infections, lymphomas and other malignancies. A black-box warning has to be taken into consideration when looking at potential serious infections such as tuberculosis. Active infections, demyelinating disorders and severe heart failure are contraindications for anti-TNF treatment. This review focuses on drug toxicity and adverse events related to infliximab treatment in IBD.     

Atorvastatin: safety and tolerability

Importance of the field: Atorvastatin is the most widely used statin administered in a variety of settings, including primary and secondary prevention of cardiovascular events, in the elderly, in patients with chronic kidney disease and in diabetic patients. Therefore, the safety and tolerability of atorvastatin is of paramount importance.

Areas covered in this review: We searched MEDLINE for literature published between 1997 and 2010 on the safety and tolerability of atorvastatin. We retrieved data from randomized controlled trials, meta-analyses, post-marketing studies, reports to regulatory bodies and case reports of rare adverse events.

What the reader will gain: The reader will gain insight into the incidence, severity, prevention and management of the major adverse effects of atorvastatin (i.e., liver function abnormalities and muscle-related side effects) overall and in special populations.

Take home message: The existing data suggest that atorvastatin is generally well tolerated across the range of its therapeutic dosage (10 – 80 mg/day).     

Atorvastatin: a safety and tolerability profile

Extensive data are available on the safety of atorvastatin from randomised clinical trials, postmarketing analyses and reports to regulatory agencies. Atorvastatin is generally well tolerated across the range of therapeutic dosages, with the exception of a slightly higher rate of liver enzyme elevations with atorvastatin 80 mg/day which does not appear to confer an increased risk of clinically important adverse events. Unlike simvastatin, atorvastatin is associated with a low incidence of muscular toxicity. It is not associated with neurological, cognitive or renal adverse effects and does not require dosage adjustment in patients with renal dysfunction, due to its favourable pharmacokinetic profile, which is unique among the statins. In patients aged > or =65 years, atorvastatin is well tolerated with no dose-dependent increase in adverse events up to the maximum daily dosage of 80 mg/day. Thus, atorvastatin is a safe and well tolerated statin for use in a wide range of patients.     

Comment and reply on: Atorvastatin: safety and tolerability

In a very short time, COX-2 enzyme inhibitors have gone from the darlings to the pariahs of the pharmaceutical industry. These drugs were developed based on the hypothesis whereby selective inhibition of the COX enzyme would lead to reduction in pain and inflammation without associated gastrointestinal and bleeding risks. However, in September 2004, rofecoxib was voluntarily removed from the market for increased cardiovascular risk and in April 2005, valdecoxib was also withdrawn, at least in part, due to excess cardiovascular risk. Celecoxib was the first COX-2 inhibitor introduced and the only remaining one on the US market. There is consequently a justified concern that cardiovascular toxicity is a class effect of all COX-2 inhibitors. This article systematically reviews the evidence surrounding COX-2 inhibitors and cardiovascular risk. Although the evidence suggests a fairly consistent cardiovascular risk with rofecoxib, the evidence for cardiovascular risk with celecoxib is more equivocal. Although isolated studies have suggested some cardiovascular risk for celecoxib, the totality of the evidence suggests that any risk is likely to be small and comparable to traditional NSAIDs. The cardiovascular risks of COX-2 inhibitors appear heterogeneous, influenced not only by the drug class, but also individual drug, dosage and patient characteristics. Specific modifying factors of the cardiovascular risk of COX-2 inhibitors including dose, concomitant drugs, individual cardiac and genetic risk profiles, will require further study.     

The safety and tolerability of zolpidem--an update

Zolpidem belongs to a new class of hypnotic agents, chemically distinct from the pre-existing ones, and has a unique neuropharmacological profile. It induces sedative/hypnotic effects in rodents at doses much lower than those for anticonvulsant and myorelaxant activities. Clinically, zolpidem is indicated for the short term treatment of insomnia. It has a short half-life (2.4h), with no active metabolite, and does not accumulate during repeated administration. The pharmacokinetic profile associated with the absence of active metabolites is consistent with the short duration of action and absence of residual effects that have been observed. Polysomnographic experience indicates that zolpidem induces a sleep pattern which is similar to that of physiological sleep, and which produces either no or only minimal effects on sleep architecture after abrupt discontinuation. Aspects of the general safety of zolpidem have been studied in data obtained from healthy volunteers and patients, both adult and elderly, during its clinical development and in post-marketing experience. Zolpidem appears to be well-tolerated in adults and in the elderly, when administered in accordance with prescribing instructions. The available data indicate that, in these circumstances, the risk of abuse or dependence is minimal.     

Review of gastrointestinal tolerability and safety of Meloxicam

Selective COX-2 inhibition relative to COX-1 has consistently been demonstrated for meloxicam in various in vitro test systems. In human platelets ex vivo COX-1-dependent thromboxane formation is partially and dose dependently inhibited, however no significant inhibition of platelet aggregation has been observed with the recommended doses of 7.5 mg and 15 mg meloxicam daily. With once daily dosing, meloxicam has demonstrated efficacy in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Meloxicam was granted its first marketing authorization in 1995 and is now available in more than 100 countries. Meloxicam has been studied in clinical trials involving more than 30 000 patients and is estimated to have been prescribed for more than 30 million patients worldwide to date. Clinically, meloxicam offers similar efficacy to recommended doses of well-established nonsteroid anti-inflammatory drugs (NSAIDs), including diclofenac, piroxicam and naproxen. Meloxicam distinguishes itself from established NSAIDs with a reduced risk of certain gastrointestinal adverse events. This has consistently been demonstrated in randomized clinical trials, large scale clinical outcome studies, pooled analyses and meta-analyses. Post-marketing experience is consistent with the safety profile established in these studies and analyses.     

Drug safety and tolerability in prophylactic migraine treatment

Introduction: Migraine is a frequent, disabling primary headache disorder, whose pathomechanism is not yet fully understood. Prophylactic treatment is advisable for migraineurs with severe or highly frequent attacks, which impair the quality of life.

Areas covered: The different types of prophylactic migraine drugs are discussed, with particular regard to potential adverse effects and safety issues. β-Adrenergic blockers, antiepileptic drugs and calcium-channel blockers are drugs widely used for migraine prevention, whereas complementary medicine and onabotulinumtoxin A can be used in selected cases.

Expert opinion: The background of the recurrence and chronification of migraine attacks has not been fully clarified, and causative preventive therapy is therefore not currently available. The tolerability and adverse effects of the currently used medications often limit their use. β-Adrenergic receptor blockers may induce adverse cardiovascular events, whereas flunarizine is frequently associated with a weight gain and depression. As most migraine sufferers are young women of child-bearing age, the use of valproate is limited. Topiramate is associated with central nervous system-related side effects. There is a need for future development of pathomechanism-based preventive drugs, and personalized therapy tailored to the patient.     

Levetiracetam safety profiles and tolerability in epilepsy patients

This review discusses the safety and tolerability of levetiracetam, as presented by the available literature, with attention paid to special populations. In Phase II/III trials, the adverse effects occurring more commonly in the treatment groups versus the placebo group were; somnolence (14.8 versus 8.4%), asthenia (14.7 versus 9.1%), infection (primarily common cold) (13.4 versus 7.5%), and dizziness (8.8 versus 4.1%). Adverse events usually appear within the first month after treatment initiation, are not dose-dependent, are mostly mild-to-moderate, generally resolve without medication withdrawal, and are transient when the medication is stopped. No significant changes in haematology and chemistry profiles or weight occurred. Hypersensitivity reactions were rare and no idiosyncratic event has been reported. Open-label studies have added patient data with other epileptic syndromes and from a wider patient pool, such as children and patients with prior psychiatric history. These studies have supported initial safety findings, but have reported increased behavioural adverse events in children and patients with a history of prior behavioural problems. Levetiracetam is proving to be safe and well-tolerated. So far, it appears to have a favourable safety profile in special populations, such as children, the elderly, and patients with hepatic dysfunction. Preliminary data in pregnancy are promising, but more data are needed on the impact of levetiracetam on the developing fetus and pharmacokinetic alterations caused in pregnancy. Adjustments in dosing are required for decreases in renal clearance.     

The gastrointestinal tolerability and safety of oral bisphosphonates

Oral bisphosphonates are effective for osteoporosis and other hyperresorptive bone disorders. Although well-tolerated in efficacy trials, some oral aminobisphosphonates have been associated with upper gastrointestinal intolerance and injury in postmarketing experience. Clinical trials often underestimate the rate of adverse events in clinical practice, and ethics prohibit direct evaluation of toxicity in high-risk patients. Accordingly, animal models and endoscopy studies of oral bisphosphonates provide valuable insight. It is unclear whether variation in ulcerogenic potential reflects differences in dosing, formulation or chemical structure. Furthermore, the clinical relevance of endoscopic lesions is uncertain. Ongoing postmarketing review will determine whether differences in endoscopic damage predict tolerability and safety in clinical practice. However, physicians and patients should consider risk factors for oesophageal injury when initiating therapy.     

Levetiracetam safety profiles and tolerability in epilepsy patients

This review discusses the safety and tolerability of levetiracetam, as presented by the available literature, with attention paid to special populations. In Phase II/III trials, the adverse effects occurring more commonly in the treatment groups versus the placebo group were; somnolence (14.8 versus 8.4%), asthenia (14.7 versus 9.1%), infection (primarily common cold) (13.4 versus 7.5%), and dizziness (8.8 versus 4.1%). Adverse events usually appear within the first month after treatment initiation, are not dose-dependent, are mostly mild-to-moderate, generally resolve without medication withdrawal, and are transient when the medication is stopped. No significant changes in haematology and chemistry profiles or weight occurred. Hypersensitivity reactions were rare and no idiosyncratic event has been reported. Open-label studies have added patient data with other epileptic syndromes and from a wider patient pool, such as children and patients with prior psychiatric history. These studies have supported initial safety findings, but have reported increased behavioural adverse events in children and patients with a history of prior behavioural problems. Levetiracetam is proving to be safe and well-tolerated. So far, it appears to have a favourable safety profile in special populations, such as children, the elderly, and patients with hepatic dysfunction. Preliminary data in pregnancy are promising, but more data are needed on the impact of levetiracetam on the developing fetus and pharmacokinetic alterations caused in pregnancy. Adjustments in dosing are required for decreases in renal clearance.     

The gastrointestinal tolerability and safety of oral bisphosphonates

Oral bisphosphonates are effective for osteoporosis and other hyperresorptive bone disorders. Although well-tolerated in efficacy trials, some oral aminobisphosphonates have been associated with upper gastrointestinal intolerance and injury in postmarketing experience. Clinical trials often underestimate the rate of adverse events in clinical practice, and ethics prohibit direct evaluation of toxicity in high-risk patients. Accordingly, animal models and endoscopy studies of oral bisphosphonates provide valuable insight. It is unclear whether variation in ulcerogenic potential reflects differences in dosing, formulation or chemical structure. Furthermore, the clinical relevance of endoscopic lesions is uncertain. Ongoing postmarketing review will determine whether differences in endoscopic damage predict tolerability and safety in clinical practice. However, physicians and patients should consider risk factors for oesophageal injury when initiating therapy.     

Monoamine oxidase inhibitors: safety and efficacy issues

Controversy has historically centered on the use of monoamine oxidase inhibitors (MAOI) in the treatment of depression because of safety and efficacy issues. Hypertensive crisis following ingestion of foods containing tyramine is the most feared problem associated with MAOI therapy. The authors conclude that only four tyramine-containing foods clearly warrant absolute prohibition, but indicate situations where moderation should apply. Although MAOI remain second-line agents in the treatment of endogenous depression, it is unclear whether MAOI or tricyclic antidepressants should be the drugs of choice in atypical depression and this question necessitates future research.     

Arsenic trioxide： safety issues and their management

Arsenic trioxide (As2O3) has been used medicinally for thousands of years. Its therapeutic use in leukaemia was described a century ago. Recent rekindling in the interest of As2O3 is due to its high efficacy in acute promyelocytic leukaemia (APL). As2O3 has also been tested clinically in other blood and solid cancers. Most studies have used intravenous As2O3, although an oral As2O3 is equally efficacious. Side effects of As2O3 are usually minor, including skin reactions, gastrointestinal upset, and hepatitis. These respond to symptomatic treatment or temporary drug cessation, and do not compromise subsequent treatment with As2O3. During induction therapy in APL, a leucocytosis may occasionally occur, which can be associated with fluid accumulation and pulmonary infiltration. The condition is similar to the APL differentiation syndrome during treatment with all-trans retinoic acid, and responds to cytoreductive treatment and corticosteroids. Intravenous As2O3 treatment leads to QT prolongation. In the presence of underlying cardiopulmonary diseases or electrolyte disturbances, particularly hypokalaemia and hypomagnesaemia, serious arrhythmias may develop, with torsades du pointes reported in 1% of cases. This may be related to a dose-dependent arsenic-mediated inhibition of potassium ion channels that compromises cardiac repolarization. Because of slow intestinal absorption, oral-As2O3 gives a lower plasma arsenic concentration, which is associated with lesser QT prolongation and hence a more favorable cardiac safety profile. As2O3 does not appear to enter the central nervous system. However, if the blood brain barrier is breached, elemental arsenic may enter the cerebrospinal fluid. As2O3 is predominantly excreted in the kidneys, and dose adjustment is required when renal function is impaired.     

Pregabalin: its efficacy, safety and tolerability profile in generalized anxiety

Pregabalin is a structural analogue of gamma-aminobutyric acid (GABA), one of the key inhibitory neurotransmitters in the brain. Its mode of action is believed to be mediated by the alpha-2-delta-1 subunit protein of voltage-gated calcium channels to bring about its anxiolytic, anticonvulsant and antinociceptive effects. Pregabalin has linear pharmacokinetics, undergoes minimal metabolism and is excreted largely unchanged. It has a mean elimination half-life of 6.3 hours. Pregabalin's anxiolytic activity in generalized anxiety disorder has been demonstrated in seven acute randomized, double-blind, placebo-controlled trials of four to eight weeks duration, and in one six-month relapse-prevention study at doses of 150-600 mg/day using twice-daily or three-times-daily regimes. The magnitude of pregabalin's anxiolytic effects was similar to that of alprazolam, lorazepam or venlafaxine. However, pregabalin had a more consistent effect on psychic and somatic anxiety factors than the active comparators. Its speed of onset was apparent within one week - similar to the benzodiazepines, but faster than that of venlafaxine. Moreover, pregabalin's anxiolytic effect was apparent in patients with moderate or severe baseline anxiety and high or low baseline severity of sub-syndromic depression. A long-term, 26-week, open-label study showed that pregabalin's anxiolytic effects were maintained, although the fixed-dose design may have contributed to a high attrition rate. Pregabalin showed less cognitive and psychomotor impairment than alprazolam, and it showed different effects on sleep architecture to the latter in terms of REM sleep latency and slow wave stage 3/4 sleep. The most frequently reported adverse events were dizziness and somnolence, although tolerance to these developed within a few weeks. Withdrawal symptoms during a one-week taper phase were mild and were similar after both acute and chronic administration.     

Safety and tolerability of glucagon-like peptide-1 receptor agonists: unresolved and emerging issues

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a mainstay of treatment options for type 2 diabetes. They contribute to lowering blood glucose levels, generally have a favorable tolerability profile, and can be used alone or in combination with other antidiabetic agents. Based on the duration of their effects, GLP-1 RAs can be divided into two classes: short-acting and long-acting. Differences exist between these sub-classes, and between each drug, in terms of pharmacokinetic and pharmacodynamic profiles. Therefore, prescribers cannot necessarily assume GLP-1 RA ‘class effects’, especially in terms of tolerability.

Areas covered: This article reviews the published data on the safety and tolerability of currently available GLP-1 RAs and, recognizing the importance of safety profiles when selecting the appropriate treatment for each patient, examines the clinical implications of the differences between the drugs in this class. Cardiovascular safety, gastrointestinal tolerability, and tolerability in elderly patients are discussed as specific areas of interest to prescribers selecting between GLP-1 RAs for their patients.

Expert opinion: Although further research is needed, the current evidence offers the potential to tailor treatment more accurately to each patient. Ultimately, this may improve adherence and persistence, thereby improving glycemic control and, in turn, reducing the risk of macro- and micro-vascular complications.     

Asenapine review,part II: clinical efficacy,safety and tolerability

Introduction: Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes.

Areas covered: The purpose of this review is to describe the clinical profile of asenapine.

Expert opinion: Asenapine's efficacy in the treatment of schizophrenia and in the acute management of bipolar manic or mixed episodes, within the recommended therapeutic dose range of 5 – 10 mg twice a day, is evidenced by a broad clinical development program. Asenapine's overall tolerability profile is notable for the potential for sedation (time-limited) and, to a lesser extent, extrapyramidal symptoms/akathisia, dizziness, and oral hypoesthesia. Asenapine's effects on weight and metabolic variables appear modest, as are its effects on the ECG QTc interval and on prolactin.