August 2011
- Azithromycin (Zithromax®, Pfizer) Interactions: Concomitant administration of macrolide antibiotics including azithromycin with P-glycoprotein substrates such as digoxin, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and digoxin are administered concomitantly, the possibility of elevated serum digoxin concentrations should be considered.
- Dasatinib (Sprycel®, Bristol-Myers Squibb) New ADR reported post-market: Pulmonary arterial hypertension.
- Desmopressin (Presinex®, Novem Healthcare) Contraindication: Thrombotic thrombocytopenic purpura (TTP).
- Esomeprazole (Nexium®, AstraZeneca) Special warnings & precautions: Hypomagnesaemia, symptomatic and asymptomatic, has been reported rarely in patients treated with proton pump inhibitors (PPIs) for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesaemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
Interactions: With the use of inhibitors of acid secretion or antacids, the absorption of digoxin can increase during treatment with esomeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (up to 30% in two out of ten subjects).
Omeprazole as well as esomeprazole act as inhibitors of CYP 2C19. Omeprazole, given in doses of 40 mg to healthy subjects in a cross-over study, increased Cmax and AUC for cilostazol by 18% and 26% respectively, and one of its active metabolites by 29% and 69% respectively.
Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampicin and St. John's Wort) may lead to decreased esomeprazole serum levels by increasing the esomeprazole metabolism.
New ADR: Hypomagnesaemia.
Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections, possibly Clostridium difficile in hospitalized patients.
- Hepatitis B vaccine (HBvaxPRO®, MSD) New ADR reported post-market: Uveitis.
- Interferon beta (Rebif®, Merck) Special warnings & precautions: Rebif® has not yet been investigated in patients with primary progressive multiple sclerosis, and should not be used in such patients.
This medicinal product contains 2.5 mg benzyl alcohol per dose. Must not be given to premature babies or neonates. May cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.
New ADR: Severe elevations of transaminase.
New ADRs reported post-market: Thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome, transient neurological symptoms (i.e. hypoaesthesia, muscle spasm, paraesthesia, difficulty in walking, musculoskeletal stiffness) that may mimic multiple sclerosis exacerbations; retinal vascular disorders (e.g. retinopathy, cotton wool spots and obstruction of retinal artery or vein), dyspnoea, hepatic failure, Stevens-Johnson syndrome.
- Levetiracetam (Keppra®, GSK) New ADRs reported post-market: Choreoathetosis, dyskinesia.
- Medroxyprogesterone (Depo-Provera®, Pfizer) Additional Warnings & Precautions for Specific Use or Formulation: In two clinical studies of 573 adult women with endometriosis, the Bone Mineral Density (BMD) effects of 6 months of subcutaneous medroxyprogesterone acetate (MPA-SC) treatment were compared to 6 months of leuprolide treatment. Subjects were then observed, off therapy, for an additional 12 months. The proportion of patients with a decrease of 5% or more in BMD was statistically significantly greater in the leuprolide group compared with MPA-SC group.
- Milrinone (Primacor® inj, sanofi-aventis) Precautions: There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reaction have been reported with intravenous milrinone therapy. Consequently, careful monitoring of the infusion site should be maintained so as to avoid possible extravasation.
New ADR: Infusion site reaction. - Norfloxacin (Nolicin®, Singapore Pharmaceutical);
- Ofloxacin (Tarivid®, Ranbaxy)
Warnings & precautions: Caution should be taken when using fluoroquinolones, including norfloxacin and ofloxacin, in patients with known risk factors for prolongation of the QT interval such as congenital long QT syndrome, concomitant use of drugs that are known to prolong the QT interval (e.g. class IA and III antiarrythmics, tricyclic antidepressants, macrolides, antipsychotics), uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia), elderly, cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
Interactions: Norfloxacin and ofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. class IA and III antiarrythmics, tricyclic antidepressants, macrolides, antipsychotics).
New ADRs: Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), prolonged ECG QT.
- Olmesartan medoxomil, hydrochlorothiazide (Olmetec Plus®, Pfizer) Special warnings & precautions: Hydrochlorothiazide, a sulphonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulphonamide or penicillin allergy.
Interactions: In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
New ADRs reported post-market: Anaphylactic reactions, peripheral oedema, diarrhoea, hyperkalaemia.
- Pregabalin (Lyrica®, Pfizer) New ADR reported post-market: Gynaecomastia.
- Somatropin (Genotropin®, Pfizer) New ADRs: Leukaemia, type 2 diabetes mellitus, paraesthesia, benign intracranial hypertension, arthralgia, myalgia, musculoskeletal stiffness, peripheral oedema, injection site reaction, decreased blood cortisol.
In the post-marketing experience rare cases of sudden death have been reported in patients affected by Prader-Willi syndrome treated with somatropin, although no causal relationship has been demonstrated. - Vardenafil (Levitra®, Bayer) Interactions: Although specific interaction studies have not been conducted, the concomitant use of other potent CYP3A4 inhibitors such as itraconazole can be expected to produce vardenafil plasma levels comparable to those produced by ketoconazole.
New ADRs include: Vasodilatation, increased muscle tone and cramping, increase in creatine phosphokinase, angioedema, allergic oedema, sleep disorder, ocular hyperaemia, myocardial infarction, ventricular tachyarrhythmias, increase in transaminases, diarrhoea.
In a pooled analysis of placebo-controlled fix-dose studies comparing 5 mg, 10 mg and 20 mg of vardenafil film-coated tablets a higher rate of dizziness was seen in elderly subjects (≥ 65 years) with doses of 10 mg or higher than in younger subjects (4.2% vs. 1.2%). Due to the vasodilatory properties of phosphodiesterase type 5 (PDE 5) inhibitors, concomitant use with alpha-blockers, may contribute to dizziness.
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July 2011
- Aztreonam (Azactam®, Bristol-Myers Squibb) Precautions: Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including Azactam®, and may range in severity from mild diarrhoea to fatal colitis. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.
- Bicalutamide (Casodex®, AstraZeneca) New ADRs: Constipation, flatulence, hirsutism, rash, chest pain, oedema, dizziness, somnolence.
Myocardial infarction with fatal outcomes and cardiac failure have been observed in a pharmaco-epidemiology study of LHRH (luteinizing hormone-releasing hormone) agonists and anti-androgens used in the treatment of prostate cancer. The risk appeared to be increased when Casodex® 50 mg was used in combination with LHRH agonists but no increase in risk was evident when Casodex® 150 mg was used as a monotherapy to treat prostate cancer.
- Carvedilol (Dilatrend®, Roche) Interactions: The concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and beta-adrenergic blockers may result in an increase in blood pressure and lower blood pressure control.
Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators. Careful monitoring of patients is recommended.
- Cetuximab (Erbitux®, Merck) Special warnings & precautions: An increased frequency of severe and sometimes fatal cardiovascular events and treatment emergent deaths has been observed in the treatment of non-small cell lung cancer, squamous cell carcinoma of the head and neck and colorectal carcinoma. In some studies (non-small cell lung cancer) association with age ≥ 65 years has been observed. When prescribing cetuximab, the cardiovascular status of the patients and concomitant administration of cardiotoxic compounds such as fluoropyrimidines should be taken into account.
Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have KRAS (oncogene Kirsten ras) mutations or for whom KRAS tumour status is unknown. Results from clinical studies show a negative benefit-risk balance in tumours with KRAS mutations.
New ADR: Aseptic meningitis.
In combination with fluoropyrimidines, the frequency of cardiac ischaemia including myocardial infarction and congestive heart failure as well as the frequency of hand-foot syndrome (palmar-plantar erythrodysaesthesia) were increased compared to that with fluoropyrimidines.
Detection of KRAS mutational status must be performed prior to the first cetuximab infusion. It is important that a validated test method is used by an experienced laboratory. - Dalteparin (Fragmin® inj, Pfizer) Special warnings & precautions: It is recommended that the platelets be counted before the initiation of dalteparin treatment and be followed regularly during treatment.
Heparin and low molecular weight heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium or taking potassium sparing drugs. Plasma potassium should be measured in patients at risk.
Long-term treatment with heparin has been associated with a risk of osteoporosis. Although this has not been observed with dalteparin the risk of osteoporosis cannot be excluded.
Elderly patients (especially patients aged 80 years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. Careful clinical monitoring is advised.
Dalteparin should not be used in patients who have suffered a recent (within 3 months) stroke unless due to systemic emboli.
Interactions: Concomitant use of drugs affecting haemostasis, such as dextran may enhance the anticoagulant effect of dalteparin.
Because non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA) analgesic/anti-inflammatory doses reduce production of vasodilatatory prostaglandins, and thereby renal blood flow and the renal excretion, particular care should be taken when administering dalteparin concomitantly with NSAIDs or high dose ASA in patients with renal failure.
Undesirable effects: Some fatal cases of haemorrhage (bleeding at any site) have been reported post-market. - Escitalopram (Lexapro®, LF Asia; Lepax®, IDS) Special warnings & precautions: Escitalopram should be discontinued if a patient develops seizures for the first time, or if there is an increase in seizure frequency (in patients with a previous diagnosis of epilepsy). Selective serotonin reuptake inhibitors (SSRIs) should be avoided in patients with unstable epilepsy, and patients with controlled epilepsy should be closely monitored.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
A meta analysis of placebo controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old. Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Interactions: Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase bleeding tendency.
New ADRs: Anorexia, suicidal ideation, suicidal behaviour, prolonged ECG QT.
Cases of suicidal ideation and suicidal behaviours have been reported during escitalopram therapy or early after treatment discontinuation.
Cases of QT-prolongation have been reported during the post-marketing period, predominantly in patients with pre-existing cardiac disease. In a double-blind, placebo-controlled ECG study in healthy subjects, the change from baseline in QTc (Fridericia-correction) was 4.3 msec at the 10 mg/day dose and 10.7 msec at the 30 mg/day dose.
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and tricyclic antidepressants (TCAs). The mechanism leading to this risk is unknown.
Pregnancy: If escitalopram is used until or shortly before birth, discontinuation effects in the newborn are possible.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur. - Gadoversetamide (Optimark®, Tyco Healthcare) Contraindications: Chronic, severe kidney disease (glomerular filtration rate, GFR <30 ml/min/1.73m2), or acute kidney injury.
Warnings: Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI) or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR <30 ml/min/1.73m2) as well as patients with acute kidney injury. Do not administer Optimark® to these patients. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 ml/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 ml/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.
Instruct the patients to contact their physician if they develop signs or symptoms of NSF following Optimark® administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness.
Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity.
Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronic kidney disease (e.g. age >60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.
Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. When administering Optimark®, do not exceed the recommended dose and allow a sufficient period of time for elimination of the drug prior to any re-administration.
New ADR reported post-market: Seizure.
The safety and effectiveness of Optimark® injection in paediatric patients have not been established. Paediatric patients may be particularly vulnerable to adverse GBCA reactions due to renal immaturity and/or unrecognized renal insufficiency. - Hyoscine (Buscopan®, Boehringer Ingelheim) Special precautions: In cases whereby severe, unexplained abdominal pain persists or worsens, or occurs together with symptoms like fever, nausea, vomiting, changes in bowel movements, abdominal tenderness, decreased blood pressure, fainting or blood in stool, medical advice should immediately be sought.
Interactions: The anticholinergic effect of drugs such as tetracyclic antidepressants, antipsychotics and other anticholinergics (e.g. atropine-like compounds) may be intensified by Buscopan®.
New ADRs: Skin reactions e.g. urticaria, rash, erythema, pruritus.
Buscopan® should not be taken on a continuous daily basis or for extended periods without investigating the cause of abdominal pain.
Pregnancy & lactation: There is limited data from the use of hyoscine butylbromide in pregnant women.
There is insufficient information on the excretion of Buscopan® and its metabolites in human milk.
As a precautionary measure, it is preferable to avoid the use of Buscopan® during pregnancy and lactation. - Lansoprazole (Prevacid®, Luen Wah) Special warnings & precautions: Hypomagnesaemia, symptomatic and asymptomatic, has been reported rarely in patients treated with proton pump inhibitors (PPIs) for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesaemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. - Lomefloxacin (Lomflox®, Zyfas) Precautions: Rare cases of torsades de pointes have been spontaneously reported during post-marketing surveillance in patients receiving quinolones, including lomefloxacin. These rare cases were associated with one or more of the following factors: age over 60, female gender, underlying cardiac disease, and/or use of multiple medications. Lomefloxacin should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalaemia, and patients receiving class IA (quinidine, pocainamide), or class III (amiodarone, sotalol) antiarrhythmic agents.
- Lopinavir, ritonavir (Kaletra®, Abbott) Warnings & precautions: Kaletra® oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of Kaletra® oral solution in this patient population has not been established.
Kaletra® oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Post-marketing life-threatening cases of cardiac toxicity (including complete atrioventricular block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving Kaletra® oral solution.
All infants administered Kaletra® should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to Kaletra® oral solution including hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnoea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and haemolysis. Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients. - Paliperidone (Invega®, J & J) Special warnings & precautions: Elderly patients with dementia-related psychosis treated with atypical antipsychotics drugs are at an increased risk of death compared to placebo. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) in these subjects revealed a risk of death in the drug-treated subjects of between 1.6 to 1.7 times that seen in placebo-treated subjects. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated subjects was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature. Invega® is not approved for the treatment of patients with dementia-related psychosis.
In placebo-controlled trials in elderly patients with dementia-treated with some atypical antipsychotic drugs, including risperidone, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischaemic attacks) including fatalities, compared to placebo.
In placebo-controlled trials in elderly patients with dementia there was a significantly higher incidence of cerebrovascular adverse events, such as stroke (including fatalities) and transient ischaemic attacks in patients (mean age 85 years, range 73-97) treated with risperidone compared to patients treated with placebo. The pooled data from six placebo-controlled trials in mainly elderly patients (>65 years of age) with dementia showed that cerebrovascular adverse events (serious and non-serious combined) occurred in 3.3% (33/989) of patients treated with risperidone and 1.2% (8/693) of patients treated with placebo. The Odds Ratio (95% exact confidence interval) was 2.96 (1.33, 7.45).
In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including Invega®. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of Invega® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue Invega® and have their WBC followed until recovery.
Undesirable effects: The designs of the two placebo-controlled, 6-week, double-blind trials in subjects with schizoaffective disorder included the option for subjects to receive antidepressants (except monoamine oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine). In the subject population evaluated for safety, 230 (55%) subjects received Invega® as monotherapy and 190 (45%) subjects received Invega® in combination with antidepressants and/or mood stabilizers. When comparing these 2 subpopulations, only nausea occurred at a greater frequency (≥3% difference) in subjects receiving Invega® as monotherapy.
Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with Invega®, the incidences of the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder, hypertonia, parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.
In the placebo-controlled, 6-week high- and low-dose study in subjects with schizoaffective disorder, dystonia, dysarthria, and nasopharyngitis occurred more frequently (i.e., a difference of at least 3%) in subjects who received higher doses of Invega® compared with subjects who received lower doses. Hypertonia occurred more frequently in subjects who received lower doses of Invega® compared with subjects who received higher doses.
For subjects with schizoaffective disorder, there was no dose-related increase in extrapyramidal symptoms (EPS) observed for parkinsonism with the Simpson-Angus scale or akathisia with the Barnes Akathisia Rating Scale. There was a dose-related increase observed with spontaneous EPS reports of hyperkinesia and dystonia and in the use of anticholinergic medications.
In the pooled data from the two placebo-controlled, 6-week studies in subjects with schizoaffective disorder, a higher percentage of Invega®-treated subjects (5%) had an increase in body weight of ≥7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of ≥7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group.
In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia and from the two placebo-controlled, 6-week studies in subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between Invega® and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, haematology, or urinalysis parameters. Similarly, there were no differences between Invega® and placebo in the incidence of discontinuations due to changes in haematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, high-density lipoprotein (HDL), low density lipoprotein (LDL), and total cholesterol measurements.
New ADRs reported post-market: Angioedema, swollen tongue, urinary incontinence, urinary retention, neonatal drug withdrawal syndrome.
Pregnancy: Neonates exposed to antipsychotic drugs (including paliperidone) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms that may vary in severity following delivery. These symptoms in the neonates may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder.
Invega® should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly. - Rivastigmine (Exelon®, Novartis) Warnings & precautions: Gastrointestinal disorders such as nausea, vomiting and diarrhoea may occur when initiating treatment and/or increasing the dose. They may respond to a dose reduction. In other cases, use of Exelon® has been discontinued. Patients who show signs or symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be managed with IV fluids and dose reduction or discontinuation if recognized and treated promptly. Dehydration can be associated with serious outcomes.
Patients with Alzheimer's disease may lose weight whilst taking cholinesterase inhibitors, including rivastigmine. The patient's weight should be monitored during therapy with Exelon®.
Patients with body weight below 50 kg may experience more adverse events and may be more likely to discontinue due to adverse events.
New ADR: Anxiety.
New ADRs reported post-market: Dehydration, aggression, restlessness, sick sinus syndrome, hepatitis.
Special populations: Patients with clinically significant renal or hepatic impairment may experience more adverse events. Dosing recommendations to titrate according to individual tolerability should be closely followed. Patients with severe liver impairment have not been studied, however, Exelon® capsules may be used in this patient population provided close monitoring is exercised. - Saxagliptin (Onglyza®, Bristol-Myers Squibb) Special warnings & precautions: A single dosage adjustment is recommended in patients with moderate or severe renal impairment. Saxagliptin should be used with caution in patients with severe renal impairment, and is not recommended for use in patients with end-stage renal disease (ESRD) requiring haemodialysis. Assessment of renal function is recommended prior to initiation of Onglyza®, and in keeping with routine care, renal assessment should be done periodically thereafter.
The dose of Onglyza® should be reduced to 2.5 mg once daily for patients with moderate or severe renal impairment. The experience in patients with severe renal impairment is very limited. Therefore, saxagliptin should be used with caution in this population.
Because the dose of Onglyza® should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of Onglyza® and periodically thereafter. Renal function can be estimated from serum creatinine using the Cockcroft-Gault formula or Modification of Diet in Renal Disease formula. - Trimetazidine (Vastarel® & Vastarel MR®, Servier) Special warnings & precautions: Trimetazidine can aggravate Parkinsonian symptoms, or cause Parkinsonian symptoms (tremor, akinesia, hypertonia), which should be investigated, especially in elderly patients.
The onset of falls may be related to arterial hypertension or to postural instability.
New ADRs: Gastralgia, dyspepsia, diarrhoea, constipation, asthenia, headaches, vertigo, sleep disorders (insomnia, somnolence), aggravation of Parkinsonian symptoms (reversible on the discontinuation of treatment); rash, pruritus, urticaria, angioedema or Quincke's oedema, acute generalized exanthematous pustulosis (AGEP) - onset of these effects can vary from a few hours to several days; orthostatic hypotension, which may be associated with fainting, vertigo or a fall, especially in elderly subjects on antihypertensive treatment; palpitations, extrasystoles, tachycardia.
The benefit of the treatment should be assessed after three months and trimetazidine should be discontinued if there is no treatment response.
Due to a lack of data on efficacy and safety, children or adolescents must not use this medicinal product.
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June 2011
- Aldesleukin (Proleukin®, Novartis) Special warnings & precautions: Proleukin® administration has been associated with capillary leak syndrome (CLS), which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS results in hypotension and reduced organ perfusion. Severe CLS resulting in death has been reported.
Interactions: Fatal Tumour Lysis Syndrome has been reported in combination with treatment with cisplatinum, vinblastine and dacarbazine. Concomitant use of the mentioned active substances is therefore not recommended.
Severe rhabdomyolysis and myocardial injury, including myocardial infarction, myocarditis and ventricular hypokinesia appear to be increased in patients receiving Proleukin® (intravenously) and interferon-alpha concurrently.
There has also been exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders observed following concurrent use of interferon-alpha and Proleukin®, including crescentic immunoglobulin A (IgA) glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome. It is recommended that patients with pre-existing auto-immune disease should not be treated with Proleukin®.
Renal or hepatic metabolism or excretion of concomitantly administered medicinal products may be altered by the administration of Proleukin®. Other medicinal products with known nephrotoxic or hepatotoxic potential should be used with caution.
Proleukin® may alter patient response to psychotropic medicinal products and therefore patients should be monitored.
It is recommended not to use contrast media within 2 weeks after treatment with Proleukin®.
Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose Proleukin® and antineoplastic agents, specifically, dacarbazine, cis-platinum, tamoxifen and interferon-alpha. These reactions consisted of erythema, pruritus, and hypotension and occurred within hours of administration of chemotherapy. These events required medical intervention in some patients.
New ADRs include: Agranulocytosis, aplastic anaemia, haemolytic anaemia, neutropenia, neutropenic fever, anaphylaxis, hypercalcaemia, diabetes mellitus, hypoglycaemia, myasthenia, coma, central nervous system lesion, intracranial/cerebral haemorrhage, leukoencephalopathy, optic neuropathy, arrhythmia, heart failure, myocarditis, cardiomyopathy, ventricular hypokinesia, cardiac arrest, pericardial effusion, cardiac tamponade, thrombophlebitis, pulmonary embolism, rectal haemorrhage, haematemesis, ascitis, activation of quiescent Crohn's disease, pancreatitis, intestinal obstruction, gastrointestinal perforation (including necrosis/gangrene), cholecystitis, liver failure with fatal outcome, Stevens-Johnson syndrome, renal failure, injection site necrosis.
Cardiac arrhythmias (supraventricular and ventricular), angina pectoris, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, oedema and mental status changes may be associated with capillary leak syndrome.
Severe manifestations of eosinophilia have been reported, involving eosinophilic infiltration of cardiac and pulmonary tissues.
Cerebral vasculitis, both isolated and in combination with other manifestations, has been reported. Cutaneous and leukocytoplastic hypersensitivity vasculitis has been reported. Some of these cases are responsive to corticosteroids.
Bacterial infection or exacerbation of bacterial infection, including septicaemia, bacterial endocarditis, septic thrombophlebitis, peritonitis, pneumonia, and local catheter site infection have been reported mainly after intravenous administration.
There have been rare reports of leukoencephalopathy associated with interleukin-2 in the literature, mostly in patients treated for HIV infection. The role of interleukin-2 in elucidating this event remains uncertain. However opportunistic infections, co-administration of interferons as well as multiple courses of chemotherapy are other factors that may pre-dispose the treated population to such event. - Diphtheria, tetanus, pertussus vaccine (Infanrix®, GSK) Warnings & precautions: Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. It is important that procedures are in place to avoid injury from faints.
- Dronedarone (Multaq®, sanofi-aventis) Special warnings & precautions: Due to limited experience in stable patients with NYHA class III heart failure or with LVEF (left ventricular ejection fraction) <35%, the use of Multaq® is not recommended.
Use of Multaq® is contraindicated in patients with NYHA class IV and unstable class III heart failure. There have been spontaneously reported events of new or worsening heart failure during treatment with Multaq®. Patients should be advised to consult a physician if they develop or experience worsening signs or symptoms of heart failure, such as weight gain, dependent oedema, or increased dyspnoea. If heart failure develops or worsens, consider the suspension or discontinuation of Multaq®.
Hepatocellular liver injury, including life-threatening acute liver failure, has been reported in patients treated with Multaq® in the post-marketing setting. Liver function tests should be performed prior to initiation of treatment with dronedarone and then repeated monthly for six months, at months 9 and 12, and periodically thereafter.
If alanine aminotransferase (ALT) levels are elevated ≥ 3 × upper limit of normal (ULN), ALT levels should be re-measured within 48 to 72 hours. If ALT levels are confirmed to be ≥ 3 × ULN, treatment with dronedarone should be withdrawn. Appropriate investigation and close observation of patients should continue until normalization of ALT.
Patients should immediately report any symptoms of potential liver injury (such as sustained new-onset abdominal pain, anorexia, nausea, vomiting, fever, malaise, fatigue, jaundice, dark urine or itching) to their physician.
Multaq® is contraindicated in patients with CrCl<30ml/min.
MAO (monoamine oxidase) inhibitors might decrease the clearance of the active metabolite of dronedarone and should therefore be used with caution.
Interactions: Dronedarone and/or its metabolites have the potential to inhibit Organic Anion Transporter (OAT); Organic Anion Transporting Polypeptide (OATP) and Organic Cation Transporter (OCT) families in vitro.
Erythromycin, an oral macrolide and a moderate CYP3A4 inhibitor, may induce torsades de pointes and, as such, is contraindicated with Multaq®. Repeated doses of erythromycin (500 mg three times a day for 10 days) resulted in an increase in steady state dronedarone exposure of 3.8 fold.
Other moderate inhibitors of the CYP3A4 are also likely to increase dronedarone exposure.
In an in vitro study MAO contributed to the metabolism of the active metabolite of dronedarone. The clinical relevance of this observation is not known.
There was a weak interaction between dronedarone and atorvastatin (which resulted in a mean 1.7-fold increase in atorvastatin exposure). In clinical trials, there was no evidence of safety concerns when dronedarone was co-administered with statins metabolized by CYP 3A4.
There was a weak interaction between dronedarone and statins transported by OATP, such as rosuvastatin (which resulted in a mean 1.4-fold increase in rosuvastatin exposure).
In clinical trials, there was no evidence of safety concerns when dronedarone was co-administered with statins metabolized by CYP 3A4.
There was a weak interaction between dronedarone and statins transported by OATP, such as rosuvastatin (which resulted in a mean 1.4-fold increase in rosuvastatin exposure).
More patients experienced clinically significant INR (international normalised ratio) elevations (≥ 5) usually within 1 to 2 weeks after starting dronedarone vs placebo in patients taking oral anticoagulants in ATHENA study. However, no excess risk of bleeding was observed in the dronedarone group.
Post-marketing cases of increased INR with or without bleeding events have been reported in vitamin K antagonists treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in patients taking vitamin K antagonists as per their label.
No interaction was observed between dronedarone and metformin, an OCT1 and OCT2 substrate.
Dronedarone does not affect the pharmacokinetics of omeprazole, a CYP 2C19 substrate.
Dronedarone does not affect the pharmacokinetics of clopidogrel and its active metabolite.
New ADRs: Congestive heart failure (CHF), liver function test abnormalities, hepatocellular liver injury (including life-threatening acute liver failure).
In the 5 placebo controlled studies, CHF occurred in the dronedarone group with rates comparable with placebo (very commonly, 11.2% vs 10.9%). This rate should be considered in the context of the underlying elevated incidence of CHF in AF (atrial fibrillation) patients. Cases of CHF have also been reported post-market. - Eletriptan (Relpax®, Pfizer) Special warnings & precautions: Eletriptan has not been systematically evaluated for use in patients with heart failure. As with other 5-HT1 (5-hydroxytryptamine type 1) receptor agonists, use in these patients is not recommended.
Excessive use of any anti-migraine medicinal product can lead to daily chronic headaches. Overuse of all triptans has been reported primarily in patients with chronic daily headache.
- Etravirine (Intelence®, J & J) Interactions: Concomitant use of Intelence® with maraviroc may cause a significant decrease in the plasma concentration of maraviroc. When Intelence® is co-administered with maraviroc (300 mg b.i.d.) in the absence of a potent CYP3A inhibitor (e.g. a boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment for Intelence® is needed.
When Intelence® is co-administered with maraviroc (150 mg b.i.d.) in the presence of a potent CYP3A inhibitor (e.g. a boosted protease inhibitor), the recommended dose of maraviroc is 150mg b.i.d. No dose adjustment for Intelence® is needed.
If Intelence® is not co-administered with a boosted protease inhibitor, then Intelence® and rifabutin can be used without dose adjustments. If Intelence® is co-administered with boosted darunavir, lopinavir or saquinavir, then rifabutin should not be coadministered due to the potential for significant reductions in etravirine exposure.
Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with Intelence®. Alternatives to clopidogrel should be considered.
New ADRs reported post-market: Myopathy, rhabdomyolysis.
- Filgrastim (Neupogen®, Roche) Undesirable effects: Reactions of cutaneous vasculitis have been reported post-market in patients with cancer receiving filgrastim (estimated reporting rate: 0.001%).
- Fluticasone (Avamys® nasal spray, GSK) Warnings & precautions: Systemic effects with nasal corticosteroids have been reported, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations.
New ADRs reported post-market: Rhinalgia, nasal discomfort (including nasal burning, nasal irritation and nasal soreness), nasal dryness. - Gabapentin (Neurontin®, Pfizer) Special warnings & precautions: Severe, life-threatening, systemic hypersensitivity reactions such as Drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking antiepileptic drugs including gabapentin.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Prior to initiation of treatment with gabapentin, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity such as fever or lymphadenopathy may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.
New ADR reported post-market: Drug rash with eosinophilia and systemic symptoms (DRESS).
- Ibuprofen (Children's Advil®, Pfizer) Interactions: Precaution is required when ibuprofen is combined with lithium due to increased plasma concentrations of lithium.
- Nilotinib (Tasigna®, Novartis) Special warnings & precautions: Treatment with Tasigna® is often associated with thrombocytopenia, neutropenia and anaemia [NCI CTC Grade 3/4 (National Cancer Institute Common Toxicity Criteria Grade 3/4)]. The occurrence is more frequent in patients with imatinib-resistant or intolerant CML (chronic myeloid leukemia) and in particular in patients with accelerated-phase CML (CML AP).
In the Phase III study in newly diagnosed Ph+ CML-CP (Philadelphia chromosome positive chronic myeloid leukemia in chronic phase) patients the change from baseline in mean time-averaged QTcF (QT interval corrected for heart rate using Fridericia's formula) interval at steady-state observed in the nilotinib 300 mg twice daily group was 6 msec. At the recommended dose of 300 mg twice daily no patient had an absolute QTcF of >480 msec and no events of Torsade de Pointes were observed.
In clinical trials, uncommon cases (0.1 to 1%) of sudden death have been reported in patients in imatinib-resistant or -intolerant CML patients in chronic and accelerated phase receiving Tasigna® with a past medical history of cardiac disease or significant cardiac risk factors. No cases of sudden deaths have been reported in the newly diagnosed Ph+ CML-CP Phase III study.
In cases whereby lipase elevations are accompanied by abdominal symptoms, doses should be interrupted and appropriate diagnostics should be considered in order to exclude pancreatitis.
New ADRs iclude: Folliculitis, pharyngitis, nasopharyngitis, rhinitis, subcutaneous abscess, anal abscess, furuncle, tinea pedis, skin papilloma, papilloma, hypersensitivity, hypercholesterolaemia, hyperlipidaemia, hyperuricaemia, gout, hypoglycaemia, dyslipidaemia, dysaethesia, photopsia, chorioretinopathy, conjunctival haemorrhage, allergic conjunctivitis, conjunctival hyperaemia, ocular hyperaemia, ocular surface disease, scleral hyperaemia, cyanosis, decrease in ejection fraction, abnormal hepatic function, contusion, acne, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discolouration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, breast induration, menorrhagia, nipple swelling, decrease in haemoglobin, increase in troponin, increase in unconjugated blood bilirubin, increase in blood insulin, increase in very low density lipoprotein, increase in blood parathyroid hormone, increase in blood pressure. - Olmesartan (Olmetec®, Pfizer) New ADRs reported post-market: Peripheral oedema, diarrhoea, anaphylactic reaction, myalgia, asthenic conditions e.g. asthenia, fatigue, lethargy, malaise.
- Ondansetron (Zofran®, GSK) Warnings & precautions: Rarely, transient ECG changes including QT interval prolongation have been reported in patients receiving ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Ondansetron should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with electrolyte abnormalities, with congenital long QT syndrome, or patients taking other medicinal products that lead to QT prolongation.
- Sertraline (Zoloft®, Pfizer) Special warnings & precautions: The risk of Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) with selective serotonin reuptake inhibitors (SSRIs) is increased with concomitant use of serotonergic drugs including fentanyl.
Coadministration of sertraline with other drugs which enhance serotonergic neurotransmission, such as fentanyl, should be undertaken with caution and avoided whenever possible due to the potential for pharmacodynamic interaction.
Cases of new onset diabetes mellitus have been reported in patients receiving SSRIs including sertraline. Loss of glycaemic control including both hyperglycaemia and hypoglycaemia has also been reported in patients with and without pre-existing diabetes. Patients should therefore be monitored for signs and symptoms of glucose fluctuations. Diabetic patients especially should have their glycaemic control carefully monitored since their dosage of insulin and/or concomitant oral hypoglycaemic drug may need to be adjusted.
False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of sertraline therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.
New ADRs reported post-market: Diabetes mellitus, hyperglycaemia, hypoglycaemia.
- Tegaserod (Zelmac®, Novartis) New ADR: Abdominal distension.
- Verapamil (Isoptin® & Isoptin® SR, Abbott) Warnings & precautions: Although impaired renal function has been shown in robust comparator studies to have no effect on verapamil pharmacokinetics in patients with end-stage renal failure, several case reports suggest that verapamil should be used cautiously and with close monitoring in patients with impaired renal function. Verapamil cannot be removed by haemodialysis.
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May 2011
- Acetylsalicylic acid (Aspirin Cardio®, Bayer) Precautions: Caution is needed in patients with impaired renal function or patients with impaired cardiovascular circulation (e.g. renal vascular disease, congestive heart failure, volume depletion, major surgery, sepsis or major haemorrhagic events), since acetylsalicylic acid may further increase the risk of renal impairment and acute renal failure.
Caution is also needed in patients suffering from severe glucose-6-phosphate dehydrogenase (G6PD) deficiency, as acetylsalicylic acid may induce haemolysis or haemolytic anaemia. Factors that may increase the risk of haemolysis are e.g. high dosage, fever or acute infections.
Side effects: Haemolysis and haemolytic anaemia in patients with severe forms of glucose-6-phosphate dehydrogenase (G6PD) deficiency have been reported. Renal impairment and acute renal failure have been reported. - Budesonide (Rhinocort Aqua® & Rhinocort® Turbuhaler®, AstraZeneca) New ADR: Anaphylactic reaction.
Lactation: Budesonide is excreted in breast milk. However, at therapeutic doses of Rhinocort Aqua® & Rhinocort® Turbuhaler® no effects on the suckling child are anticipated. Breastfeeding can be considered if the potential benefit outweighs any potential risks. - Erythromycin (Stiemycin® gel & solution, GSK) Warnings & precautions: Erythromycin should be used with caution in patients with a known sensitivity or allergy to any ingredients.
Concomitant topical acne therapy should be used with caution since a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating or abrasive agents. If irritancy or dermatitis occurs, erythromycin should be discontinued.
Cross-resistance and cross-sensitivity with other antibiotics of the macrolide group and with clindamycin may occur.
The use of antibiotic agents may be associated with the overgrowth of antibiotic-resistant organisms. If this occurs, discontinue use.
Erythromycin should be used with caution in patients with or with a history of regional enteritis ulcerative colitis, antibiotic-associated colitis (including pseudomembranous colitis).
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including erythromycin, and may range in severity from mild to life-threatening. Although this is unlikely to occur with topically applied erythromycin, if prolonged or significant diarrhoea occurs or the patient experience abdominal cramps, treatment should be discontinued immediately and the patient investigated further, as the symptoms may indicate antibiotic-associated colitis.
Treatment may be continued for up to a maximum of 6 months. If there is no improvement after 6 to 8 weeks, or if the condition becomes worse, treatment should be discontinued.
Interactions: Clindamycin and erythromycin have been shown to be antagonistic in vitro.
New ADRs: Application site stinging & application site erythema (especially on initiation of treatment).
New ADRs reported post-market: Allergic reaction, diarrhoea, abdominal discomfort, upper abdominal pain, rash, urticaria, pruritus, facial oedema.
Pregnancy & lactation: There is limited data on the use of topical erythromycin in pregnant women. No effects during pregnancy are anticipated since systemic exposure to erythromycin is very limited. However, topical erythromycin should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus.
Percutaneous absorption of erythromycin is very limited, however, it is not known whether erythromycin is excreted in human milk after topical application. Erythromycin is excreted in human milk following oral and parenteral administration. Topical erythromycin should be used during lactation only if the expected benefit justifies the potential risk to the infant. If used during lactation, erythromycin should not be applied to the breast area to avoid accidental ingestion by the infant. - Gadobenate dimeglumine (MultiHance®, IDS) Special warnings & precautions: Prior to administration of MultiHance®, it is recommended that all patients are screened for renal dysfunction by obtaining laboratory tests.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium containing contrast agents in patients with acute or chronic severe renal impairment (GFR<30ml/min/1.73m2).
Patients undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group. As there is a possibility that NSF may occur with MultiHance®, it should therefore be avoided in patients with severe renal impairment and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI (magnetic resonance imaging).
As the renal clearance of gadobenate dimeglumine may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.
Special populations: Use of MultiHance® should be avoided in patients with severe renal impairment (GFR< 30 ml/min/1.73m2) and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI. If use of MultiHance® cannot be avoided, the dose should not exceed 0.1 mmol/kg body weight when used for MR of the brain and spine or MR-angiography and should not exceed 0.05 mmol/kg body weight when used for MR of the liver. More than one dose should not be used during a scan. Due to the lack of information on repeated administration, MultiHance® injections should not be repeated unless the interval between injections is at least 7 days.
No dosage adjustment is considered necessary. Caution should be exercised in elderly patients.
Pregnancy & lactation: There is no data from the use of gadobenate dimeglumine in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses. MultiHance® should not be used during pregnancy unless the clinical condition of the woman requires use of gadobenate dimeglumine.
Gadolinium containing contrast agents are excreted into breast milk in very small amounts. At clinical doses, no effects on the infant are anticipated due to the small amount excreted into milk and poor absorption from the gut. Continuing or discontinuing breast feeding for a period of 24 hours after administration of MultiHance® should be at the discretion of the doctor and lactating mother. - Influenza vaccine (Fluad®, Novartis) Precautions: A protective response may not be elicited in all vaccines.
New ADRs reported post-market: Asthenia, Influenza-Like Illness (ILI), pain in the extremity, muscular weakness, lymphadenopathy. - Ipratropium, fenoterol (Berodual® & Berodual® N, Boehringer Ingelheim) Special warnings & precautions: In patients with bronchial asthma Berodual® & Berodual® N should be used only on an as-needed basis. In patients with mild chronic obstructive pulmonary disease (COPD) on demand (symptom-oriented) treatment may be preferable to regular use.
Berodual® & Berodual® N should be used with caution in patients predisposed to narrow-angle glaucoma, or with pre-existing urinary outflow tract obstruction (e.g. prostatic hyperplasia or bladder-neck obstruction).
The use of Berodual® & Berodual® N may lead to positive results with regard to fenoterol in tests for nonclinical substance abuse, e.g. in the context of athletic performance enhancement (doping).
Berodual® solution for inhalation contains the preservative benzalkoniumchloride and the stabiliser disodium ededate dihydrate. When inhaled these components may cause bronchospasm in sensitive patients with hyper reactive airways.
New ADRs: Dysphonia, agitation, mental disorder, conjunctival hyperaemia, halo vision, dry throat, stomatitis, glossitis, mouth oedema, muscular weakness. - Lamotrigine (Lamictal®, GSK) Warnings & precautions: Rash has been reported as part of a hypersensitivity syndrome associated with a variable pattern of systemic symptoms including fever, lymphadenopathy, facial oedema, abnormalities of the blood and liver and aseptic meningitis.
Therapy with Lamictal® increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.
Post-marketing cases of aseptic meningitis have been reported in paediatric and adult patients taking Lamictal® for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of Lamictal®. Re-exposure resulted in a rapid return of symptoms (from 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Lamotrigine should not be restarted in patients who have discontinued due to aseptic meningitis associated with prior treatment of lamotrigine.
Some of the patients treated with Lamictal® who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.
Cerebrospinal fluid (CSF) analysed at the time of clinical presentation in reported cases was characterised by a mild to moderate pleocytosis, normal glucose levels and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction.
Interactions: Aripiprazole does not significantly inhibit or induce glucuronidation of lamotrigine.
In a study of 18 adult patients with bipolar I disorder, receiving an established regimen of lamotrigine (>/=100 mg/day), doses of aripiprazole were increased from 10 mg/day to a target of 30 mg/day over a 7 day period and continued once daily for a further 7 days. An average reduction of approximately 10% in Cmax and AUC of lamotrigine was observed. An effect of this magnitude is not expected to be of clinical consequence. - Lenograstim (Granocyte®, sanofi-aventis) Warnings & precautions: Transient cytogenetic changes have been observed in healthy donors following use of G-CSF (granulocyte-colony stimulating factor). The implications of these changes are not known.
Granocyte® contains phenylalanine, which can be harmful to patients with phenylketonuria. - Measles, mumps, rubella & varicella vaccine live (Priorix-Tetra®, GSK) Special warnings & precautions: Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. It is important that procedures are in place to avoid injury from faints.
Cases of worsening of thrombocytopenia and recurrence of thrombocytopenia in subjects who suffered thrombocytopenia after the first dose have been reported following vaccination with live measles, mumps and rubella vaccines. In such cases, the risk-benefit of immunising with Priorix-Tetra® should be carefully evaluated. - Metformin, vildagliptin (GalvusMet®, Novartis) New ADR reported post-market: Pancreatitis.
- Nevirapine (Viramune®, Boehringer Ingelheim) Special warnings & precautions: Viramune® suspension contains the excipients methyl parahydroxy benzoate and propyl parahydroxy benzoate, which may cause allergic reactions (possibly delayed).
New ADRs: Drug rash with eosinophilia and systemic symptoms, anaphylactic reaction, hypertransaminasaemia, increased transaminases, increased hepatic enzyme.
- Ribavirin (Copegus®, Roche) Special warnings & precautions: The safety and efficacy of Pegasys® and Copegus® treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on Pegasys®, alone or in combination with Copegus®.
New ADRs reported post-market: Pure red cell aplasia (PRCA) and homicidal ideation. - Sodium valproate (Epilim®, sanofi-aventis) Special warnings: A decision to use Epilim® in women of childbearing potential should not be taken without specialist's neurological advice, and only if the benefits of its use outweigh the potential risks of congenital anomalies to the unborn child. This decision is to be taken; before Epilim® is prescribed for the first time as well as before a woman already treated with valproic acid is planning pregnancy. Adequate counselling should be made available to all women of childbearing potential regarding the risks associated with pregnancy.
Interactions: Rifampicin may decrease the valproate blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
Concomitant administration of valproate and topiramate has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring of signs and symptoms is advised in particularly at risk patients such as those with pre-existing encephalopathy.
New ADRs: Pure red cell aplasia, agranulocytosis, angioedema, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.
Pregnancy & lactation: During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia carry a particular risk of death for mother and for the unborn child.
Data suggests that the use of valproate is associated with a greater risk of certain types of malformations (in particular neural tube defects) than some other antiepileptic drugs. Both valproate monotherapy and valproate as part of polytherapy are associated with abnormal pregnancy outcome. Available data suggests that antiepileptic polytherapy including sodium valproate is associated with a higher risk of abnormal pregnancy outcome than sodium valproate monotherapy.
The interpretation of the observed findings in offspring born to mothers with epilepsy treated with sodium valproate remains uncertain, in the view of possible confounding factors such as low maternal IQ, genetic, social, environmental factors and poor maternal seizure control during pregnancy.
Autism spectrum disorders have also been reported in children exposed to valproate in utero.
Specialist advice is required and physicians are strongly encouraged to discuss reproductive issues with their patients before Epilim® is prescribed for the first time or a woman already treated with Epilim® is planning a pregnancy.
Although there appears to be no contraindication to breastfeeding, physicians are advised that in any individual case, consideration should be given to the safety profile of Epilim®, specifically haematological disorders. - Telmisartan; Telmisartan, Hydrochlorothiazide (Micardis®; Micardis® Plus, Boehringer Ingelheim) New ADR reported with telmisartan monotherapy: Hypoglycaemia (in diabetic patients).
Most cases of hepatic function abnormal / liver disorder from post-marketing experience with telmisartan occurred in patients in Japan.
New ADR reported post-market with Micardis® Plus: Exacerbation or activation of systemic lupus erythematosus.
Angioedema, with fatal outcome, has been reported with telmisartan and Micardis® Plus. - Terbutaline (Asmalin®, Sunward; Butylin®, Goldplus) Contraindication: Oral terbutaline sulfate is contraindicated in the treatment of acute or maintenance tocolysis.
Warnings & precautions: There are no adequate and well-controlled studies of terbutaline sulfate in pregnant women.
Published animal studies show that rat offspring exhibit alterations in behaviour and brain developement, including decreased cellular proliferation and differentation when dams were treated subcutaneously with terbutaline during the late stage of pregnancy and lactation period. Terbutaline exposures in rat dams were approximately 6.5 times the common human dose in adults of 15 mg/day, on a mg/m² basis.
Oral tebutaline sulfate has not been approved and should not be used for acute or maintenance tocolysis. In particular, terbutaline sulfate should not be used for tocolysis in the outpatient or home setting. Serious adverse reactions, including death, have been reported after administration of terbutaline sulfate to pregnant women. In the mother, these adverse reactions include increased heart rate, transient hyperglycaemia, hypokalaemia, cardiac arrhythmias, pulmonary oedema and myocardial ischaemia. Increased foetal heart rate and neonatal hypoglycaemia may occur as a result of maternal administration.
Terbutaline sulfate should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
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