Safety-related issues resulting in labelling amendments made to the local package inserts are listed below. Please note that there might be lag time in the availability of the package insert which reflect the latest change(s). Please refer to the company representative for details.
April 2007
- Adalimumab (Humira®, Abbott) Under "Precautions", it is stated that there is limited safety experience of surgical procedures in patients treated with Humira®. Long half-life of adalimumab should be taken into consideration if a surgical procedure is planned. Patient who requires surgery while on Humira® should be closely monitored for infections & appropriate actions taken. Limited safety experience in patients undergoing arthroplasty while receiving Humira.
Under "Adverse Reactions", new "Liver Enzyme Elevations" section added describing ALT elevations in several clinical trials comparing monotherapy and combined therapy with methotrexate as well as patients with psoriatic arthritis and those with RA.
New ADRs: interstitial lung disease including pulmonary fibrosis, reactivation of hepatitis B & demyelinating disorders e.g. optic neuritis.
- Allopurinol (Zyloric®, GSK) Dose reductions of didanosine may be required when used concomitantly with Zyloric as plasma didanosine Cmax & AUC may be doubled with concomittant treatment.
- Atenolol/ Chlorthialidone (Tenoret 50®, Tenoretic®, AstraZeneca) New ADRs: pancreatitis & impotence.
- Fludarabine (Fludara®, Zuellig) Patients undergoing treatment with Fludara® should be closely monitored for response & toxicity. Individual dosing should be carefully adjusted according to the observed haematological toxicity. Please refer to PI for details on dosing regimen.
Fludara® is contraindicated in decompensated haemolytic anaemia.
- Human Chorionic gonadotrophin (hCG) (Pregnyl®, Organon) Under "Special warnings", it is stated that:
-Early confirmation of intrauterine pregnancy is important for women undergoing assisted reproduction particularly IVF as they often have tubal abnormalities & incidence of ectopic pregnancies might be increased.
-Rates of pregnancy loss in women undergoing ART are higher than in the normal population.
-Presence of uncontrolled non-gonadal endocrinopathies e.g. thyroid, adrenal or pituitary disorders, should be ruled out.
-Women prone to thrombosis may have increased risk of venous or arterial thromboembolic events during or following treatment with gonadotropins. Pregnancy itself also carries increased risk of thrombosis.
-Pregnyl should not be used for body weight reduction as hCG has no effect on fat metabolism & distribution or appetite
Pregnyl® must not be used during lactation. New ADRs: bruising, pain, redness, swelling & itching at site of injection; pain &/or rash at injection site & rarely generalized rash or fever; unwanted ovarian hyperstimulation & thromboembolism in females (rare).
- Lignocaine (Xylocaine® Injection & Spray, AstraZeneca) Under "Precautions", it is stated that:
-Central nerve blocks may cause cardiovascular depression in the presence of hypovolaemia. Epidural anaesthesia may lead to hypotension & bradycardia; use with caution when cardiovascular function is impaired.
-Fetal tachycardia frequently follows paracervical block & may be associated with fetal acidosis & hypoxia.
-Patients being treated with anti-arrhythmic drugs class III e.g. amiodarone, should be under close surveillance & ECG monitoring since cardiac effects may be additive.
Under "Drug interactions", it is stated that lignocaine should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics like certain anti-arrhythmic drugs e.g. mexiletin.
New ADRs: hyperacusis, paraesthesia circumoral, numbness of tongue, cardiac arrhythmias, hypertension, shock, peripheral nerve injury & arachnoiditis.
Xylocaine® spray should not be used on plastic cuffs of endotracheal tubes (ETT).
- Pemetrexed (Alimta®, Eli Lilly) It is warned that pemetrexed can suppress bone marrow function as manifested by pancytopenia. New ADR: colitis (rare).
- Piroxicam (Feldene®, Pfizer) Undesirable effects may be minimized by using minimum effective dose for the shortest duration necessary to control symptoms.
Piroxicam is contraindicated in the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery, severe renal & hepatic failure, severe heart failure.
Under "Special warnings", it is stated that:
-Use of piroxicam with concomitant NSAIDs including COX-2 inhibitors should be avoided. NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction & stroke, which can be fatal. Risk may increase with duration of use & in patients with known risk.
-Use is cautioned and close monitoring recommended in patients with compromised cardiac function & other conditions predisposing to, or worsened by, fluid retention.
-NSAIDs, including piroxicam, can cause serious gastrointestinal (GI) adverse events including inflammation & perforation of the stomach, small intestine, or large intestine, which can be fatal. Treatment should be withdrawn when GI bleeding or ulceration occurs. Patients at risk include the elderly, those with cardiovasular disease, those on concomitant aspirin, or those with prior history of, or active GI disease.
-Caution when initiating treatment in patients with severe dehydration & in patients with kidney disease. Lower doses of piroxicam should be considered with close monitoring in these patients.
-Stevens Johnson syndrome & toxic epidermal necrolysis are rarely reported. The highest risk for such skin reactions is early in the course of therapy (mostly in first month of treatment).At the first appearance of skin rash, mucosal lesions, or hypersensitivity, piroxicam should be stopped.
Piroxicam may interact with:1) diuretics & other anti-hypertensive drugs such as angiotensin-converting enzyme (ACE) inhibitors & angiotensin II antagonists (AIIA), aggravating the deterioration of renal function in elderly and those with impaired renal function;2) cardiac glycosides (digoxin & digitoxin) to exacerbate cardiac failure, reduce glomerular filtration rate & increase plasma glycoside levels; 3) cholestyramine 4) corticosteroids, increasing risk of GI ulcer and bleeds; 5) Cyclosporin, increased nephrotoxicity risk; 6) Methotrexate; 7) Tacrolimus, increased nephrotoxicity.
New ADRs: anorexia, aseptic meningitis, dermatitis exfoliative, erythema multiforme.
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March 2007
- Bevacizumab (Avastin®, Roche) Avastin® should not be used in the pediatric group until further data becomes available.
Under "Special Warnings"-
1) caution should be exercised when treating patients with metastatic carcinoma of the colon or rectum due to increased risk for gastrointestinal perforations.
2) Avastin® should be discontinued in patients who develop hypertensive encephalopathy.
3) Avastin® should not be used in patients with CNS metastases.
4) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been rarely reported in Avastin®-treated patients & treatment includes control of hypertension with discontinuation of Avastin®.
Experience from Clinical Trials showed an increased incidence of hypertension in patients treated with Avastin® rarely resulted in discontinuation of Avastin treatment or hospitalization. New ADRs (clinical trials): thrombocytopenia, decreased blood potassium & prolonged prothrombin time.
- Diphtheria, tetanus, pertussis toxoids (Infanrix®, Infanrix-IPV®, GSK) It is warned that in children with progressive neurological disorders like infantile spasms, uncontrolled epilepsy or progressive encephalopathy, it is better to defer pertussis immunization until the condition is corrected or stable. Decision to give pertussis vaccine must be made on an individual basis after careful consideration of risks & benefits.
New ADRs: Diffuse swelling of the injected limb, sometimes involving adjacent joint (uncommon).Swelling more likely when children primed with acellular pertussis vaccines vs whole cell vaccine; swelling may be more frequent when booster dose is administered between 4 & 6 years resolving over an average of 4 days. Swelling of the entire injected limb has been reported.
- Heparin Sodium (Heparin Injection®, Mayne Pharma) Under "Precautions", it is stated that when neuraxial (epidural/spinal) anaesthesia or spinal puncture is employed, patients on or scheduled to be on heparin are at risk of developing an epidural or spinal haematoma which can result in long term or permanent paralysis. Risk of haematoma is increased by use of indwelling epidural catheters for administration of analgesia or by concomitant use of drugs affecting haemostasis e.g. NSAIDs, platelet inhibitors, anticoagulants, & traumatic or repeated epidural or spinal puncture. Physicians should consider potential benefit vs risk before neuraxial intervention in these patients & patients should be frequently monitored for signs & symptoms of neurological impairment which requires urgent treatment.
- Lamotrigine (Lamictal®, GSK) Caution is required when treating patients with a history of allergy or rash to other antiepileptic drugs as the frequency of non-serious rash after treatment with Lamictal® was approximately three times higher in these patients than in those without such history.
Whilst the data provides no evidence for a substantial increase in the overall risk of major birth malformations associated with Lamictal use, one registry has reported an increase in the risk of isolated oral cleft malformations. This increased risk has not been confirmed in a pooled analysis of data from six other registries.
- Mycobacterium bovis (BCG Vaccine SSI®, Diethelm) If inadvertent systemic or persistent local infection with BCG vaccine occurs, expert advice should be sought regarding appropriate treatment regimen.
- Nadroparin (Fraxiparine®, GSK) New ADRs: thrombocytosis, anaphylactoid reaction, injection site reaction, calcinosis at injection site.
Patients with impaired renal function are at increased risk of bleeding & should be treated with caution when giving nadroparin.
- Pregabalin (Lyrica®, Pfizer) It is warned that after discontinuation of short-term & long-term treatment with pregabalin, withdrawal symptoms e.g. insomnia, headache, nausea, diarrhoea, have been observed. Congestive heart failure has been observed post-market and pregabalin should be used with caution in CHF patients
New ADRs: allergic reaction, hypersensitivity, congestive heart failure, diarrhoea & pruritus have been reported.
Treatment with Lyrica® was associated with creatine kinase elevations (in pre-clinical trials). The causality is not completely understood. Lyrica® should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur with of symptoms of myopathy.
- Terbutaline (Bricanyl®, AstraZeneca) New ADRs: nausea & tachycardia. As for all beta 2-agonists, cardiac arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia & extrasystoles have been rarely reported.
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February 2007
- Bicalutamide (Casodex®, AstraZeneca) Under "Precautions", it is stated that hepatic failure has rarely been observed.
January 2007
- Alendronate (Fosamax®, MSD) Under "Precautions", it is stated that localized osteonecrosis of the jaw (ONJ) has occurred in patients with postmenopausal osteoporosis.
- Ambroxol (Mucosolvan®, Boehringer Ingelheim) Under "Warnings", it is stated that as Mucosolvan® contains sorbitol, those with rare hereditary fructose intolerance should not take it. Very rarely, severe skin lesions have been reported with Mucosolvan® & use must be discontinued. New ADRs like vomiting & heartburn, are added. The use of Mucosolvan® in the first trimester of pregnancy is not recommended.
- Clobutinol (Silomat®, Boehringer Ingelheim) Silomat® is contraindicated in patients with known congenital Long QT syndrome & rare hereditary conditions (like fructose intolerance) that may be incompatible with an excipient of the product e.g. sorbitol. The sorbitol in the syrup may also have laxative effect.
Side effects like somnolence & hallucinations (primarily seen in children & geriatric patients) are added. Clobutinol may lengthen QT interval in patients with congenital Long QT syndrome & very rarely, Torsade de Pointes can occur.
[Note: Silomat® has been volunarily withdrawn by Boehringer Ingelheim on 4 Sep 2007]
- Clomipramine (Anafranil® SR, Novartis) Indicated for children & adolescents in the treatment of obsessive-compulsive syndromes, nocturnal enuresis (only in patients over age of 5 & if organic causes excluded). When initiating clomipramine for nocturnal enuresis, weigh benefits vs risks & potential alternative therapies should be considered. No experience available in children younger than 5 years old. No sufficient safety & efficacy evidence of Anafranil® in treatment of depressive states, phobias, panic attacks, cataplexy accompanying narcolepsy & chronic painful conditions in children & adolescents (0-17 years old) hence use not recommended.
As a precaution against possible QTc prolongation, any increase in dose should be made with caution if drugs that prolong QT interval are co-administered.
Under "Special warnings", it is stated that antidepressants increased the risk of suicidal thinking & behaviour in short-term studies in children & adolescents with depressive disorders & other psychiatric disorders hence all patients being treated with Anafranil® should be observed for suicidality & other psychiatric symptoms & if needed, to discontinue Anafranil®. The smallest quantity of tablets or capsules should be prescirbed to reduce the risk of overdose.
Anafranil® should be used with caution in patients with a history of increased intraocular pressure, narrow-angle glaucoma, or urinary retention e.g. diseases of the prostate.
Medication should be tapered before discontinuation of treatment.Anafranil® coated tablets contain lactose & sucrose hence patients with hereditary galactose & fructose intolerances, severe lactase deficiency, sucrase-isomaltase insufficiency or glucose-galactose malabsorption should not take them.
- Fondaparinux (Arixta®, GSK) In patients undergoing surgery, the timing of the first dose of Arixtra® requires strict adherence.
Under "Warnings", it is added that Arixtra® does not bind to platelet factor 4 and doesn't cross-react with sera from patients with Heparin Induced Thrombocytopenia (HIT)-type II.
Some new ADR terms include post-operative wound infections, thrombocythaemia, abnormal platelets, coagulation disorder, hypokalaemia, anxiety, bilirubinaemia, syncope, leg pain.
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