Health Science Authority

Safety-related Product Label Amendments
(January – April 2011)

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April 2011

  • Cetirizine (Rizine®, MD Pharmaceuticals) Contraindications:
    - Hypersensitivity to hydroxyzine & piperazine derivatives

    - Renal failure

    - Pregnancy & lactation

    - Children under 6 years of age

    - Concomitant administration with theophylline and ritonavir

    Dosage should be reduced in patients with renal impairment.
  • Everolimus (Certican®, Novartis) Special warnings & precautions: Patients on a regimen of immunosuppressive medicinal products, including Certican®, are at increased risk of developing infections especially infections with opportunistic pathogens (bacterial, fungal, viral, protozoal). Among opportunistic conditions to which immunosuppressed patients may be vulnerable are polyomavirus infections which include BK virus-associated nephropathy which can lead to kidney graft loss and the potentially fatal JC virus-associated progressive multiple leukoencephalopathy (PML). These infections, often related to total immunosuppressive burden, should be considered in the differential diagnosis of immunosuppressed patients with deteriorating kidney graft function or neurological symptoms.

    Patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects as described in the respective prescribing Information of these medicinal products.

    Certican® has been associated with the development of angioedema. In the majority of cases reported patients were receiving ACE inhibitors as co-medication.

    Certican® with full-dose ciclosporin increases the risk of renal dysfunction. Reduced doses of ciclosporin are required for use in combination with Certican® in order to avoid renal dysfunction.

    The use of Certican® with ciclosporin in de-novo renal transplant recipients has been associated with increased proteinuria. The risk increases with higher everolimus blood levels.

    In renal transplant patients with mild proteinuria while on maintenance immunosuppressive therapy including a calcineurin inhibitor (CNI) there have been reports of worsening proteinuria when the CNI is replaced by Certican®. Reversibility has been observed with interruption of Certican® and reintroduction of the CNI. The safety and efficacy of conversion from CNI to Certican® in such patients have not been established.

    Patients receiving Certican® should be monitored for proteinuria.

    An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, mostly within the first 30 days post-transplantation.

    Certican®, like other mTOR inhibitors, can impair healing increasing the occurrence of post-transplant complications such as wound dehiscence, fluid collections and wound infection which may require further surgical attention. Lymphocele is the most frequently reported such event in renal transplant recipients and tends to be more frequent in patients with higher body mass index. The frequency of pericardial and pleural effusion is increased in cardiac transplant recipients.

    The concomitant administration of Certican® with a CNI may increase the risk of CNI-induced haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.

    Certican® has been shown to increase the risk of new onset diabetes mellitus after transplant. Blood glucose concentrations should be monitored closely in patients treated with Certican®.

    There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors. Preclinical toxicology studies having shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Certican® therapy.

    Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine.

    New ADRs: Pancytopenia, pericardial effusion, increased follicle-stimulating hormone (FSH), new onset diabetes mellitus, graft thrombosis, leukocytoclastic vasculitis, pleural effusion, stomatitis/mouth ulceration, proteinuria, impaired healing, erectile dysfunction.
  • Influenza vaccine (Agrippal®, Novartis) New ADRs reported post-market: Transient lymphadenopathy, paraesthesiae, febrile convulsions.

  • Itraconazole (Sporanox®, J & J) New ADRs reported post-market: Dyspnoea, acute generalized exanthematous pustulosis.

  • Measles, mumps & rubella vaccine live (Priorix®, GSK) Warnings & precautions: 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® should be carefully evaluated.
  • Solifenacin (Vesicare®, GSK) Precautions: Angioedema with airway obstruction has been reported in some patients on solifenacin succinate. If angioedema occurs, solifenacin succinate should be discontinued and appropriate therapy and/or measures should be taken.

    Adverse effects: In addition to the adverse events listed above, worldwide post-marketing experience with Vesicare® has indicated that hallucinations, confusion, hypersensitivity reactions (including angioedema), skin reactions (pruritis, urticaria) and Torsade de Pointes have been reported in association with solifenacin use; however the frequency of events and the role of solifenacin in their causation cannot be reliably determined from post-marketing experience.

  • Strontium ranelate (Protos®, Servier) New ADRs: Alopecia, bone marrow failure, eosinophilia (in association with hypersensitivity skin reactions), lymphadenopathy (in association with hypersensitivity skin reactions), increased blood creatine phosphokinase (CPK).

  • Telbivudine (Sebivo®, Novartis) Contraindications: Combination of telbivudine 600 mg daily with pegylated interferon alfa-2a, 180 micrograms once weekly.

    Special warnings & precautions: In one study, an increased risk of developing peripheral neuropathy has been observed with the combination use of telbivudine, 600 mg daily, and pegylated interferon alfa-2a, 180 micrograms once weekly compared to telbivudine or pegylated interferon alfa-2a, 180 micrograms once weekly alone. Such risk cannot be excluded for other dose regimens of pegylated interferon alfa-2a, or other alfa interferons (pegylated or standard).

  • Timolol (Nyolol®, Novartis) Contraindications: Corneal diseases, severe allergic rhinitis and bronchial hyperreactivity.

    Special warnings & precautions: Like other topically applied ophthalmic drugs, Nyolol® is absorbed systemically and systemic effects seen with oral beta-blockers may occur.

    Nyolol® should be used with caution in patients with metabolic acidosis.

    During anaesthesia severe bradycardia and hypotension have been observed in some patients using beta-blockers. The anaesthesiologist should be informed when the patient is receiving Nyolol®. A gradual withdrawal of Nyolol® over 1 to 2 weeks is recommended in high risk patients (including patients with coronary heart disease) prior to scheduled surgery. Sudden withdrawal of Nyolol® may lead to exacerbation of angina and development of hypertension and arrhythmias; Nyolol® should therefore be discontinued at least 24 to 48 hours prior to surgery.

    Nyolol® may cause worsening systolic heart failure or new heart failure in patients who depend on high sympathetic drive to maintain cardiac output. Cardiac failure should be adequately controlled before beginning therapy with patients with a history of severe cardiac disease should be monitored for early signs of possible cardiac failure.

    Therapy with beta-blockers may mask certain symptoms of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.

    Concomitant use of amisulpride with Nyolol® may lead to increased risk of ventricular arrhythmia, particularly torsades de pointes. Therefore, caution is recommended in patients with pre-existing bradycardia.

    In patients with severe renal impairment on dialysis, treatment with Nyolol® has been associated with pronounced hypotension.

    Patients suspected of developing thyrotoxicosis should be watched carefully to avoid abrupt withdrawal of beta-blocking agents, which might cause a thyroid storm.

    While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual dose of epinephrine used to treat anaphylactic reactions.

    Concomitant administration of monoamine oxidase (MAO) inhibitors should be avoided.

    Nyolol® should not be used with another topical beta-blocker.

    Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy.

    Close monitoring of cardiac function and observation of the patient for bradycardia or heart block is advised when amiodarone and a beta adrenergic blocker are coadministered.

    In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic.

    Nyolol® eye drops contain benzalkonium chloride as a preservative. Benzalkonium chloride may cause eye irritation and is known to discolour soft contact lenses. Therefore avoid contact with soft contact lenses. Remove contact lenses prior to drug application and wait at least 15 minutes before reinsertion. Nyolol® is generally well tolerated with glaucoma patients wearing conventional hard contact lenses.

    As with any glaucoma treatment, regular examination of the intraocular pressure and cornea is recommended.

    Safety and efficacy in paediatric population have not been established.

    Interactions: Although Nyolol® alone has little or no effect on pupil size, mydriasis has occasionally been reported when Nyolol® is given with epinephrine.

    The effect on intraocular pressure or the known effects of systemic beta-blockade may be exaggerated when Nyolol® is given to patients already receiving an oral beta-blocking agent.

    As timolol maleate is absorbed systemically the following interactions (as those seen with systemic beta-blockers) may occur:
    Coadministration of Nyolol® with class I anti-arrhythmic drugs (e.g. disopyramide, quinidine, propafenone) and amiodarone may have potentiating effect on atrial-conduction abnormalities time and induce negative inotropic effect.

    The nature of any cardiovascular adverse effects varies depending on the type of calcium-channel blocker used. Dihydropyrine derivatives, such as nifedipine, may lead to hypotension, whereas verapamil or diltiazem tend to cause AV conduction disturbances or left ventricular failure when used with beta-blocker.

    Beta-adrenergic blocking agents may exacerbate the “rebound hypertension” which can follow the withdrawal of clonidine.

    Attenuation of the reflex tachycardia and increase of the risk of hypotension may occur when anaesthetic drugs are coadministered with a beta blocker. The anaesthesiologist should be informed when the patient is receiving Nyolol®.

    Association of digitalis glycosides with beta-blockers may increase auriculo-ventricular conduction time.

    Close observation of the patient is also recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

    Cimetidine and hydralazine may induce increased plasma level of timolol maleate.

    Parasympathomimetics increase the risk of bradycardia.

    Amisulpride Increases the risk of ventricular arrhythmia, particularly torsades de pointes.

    Cases of potentiated systemic beta-blockade (e.g. decreased heart rate, depression) have been reported with CYP2D6 inhibitors (e.g. quinidine, SSRIs).

    Prolongation of the QT interval may occur with mefloquine.

    Nyolol® may intensify the blood sugar lowering effect of insulin and oral antidiabetic drugs, and beta-adrenergic blockade may prevent the appearance of signs of hypoglycaemia (tachycardia).

    New ADRs include: Systemic lupus erythematosus, signs and symptoms of allergic reactions including angioedema; hypoglycaemia, memory loss, syncope, cerebrovascular accident, cerebral ischaemia, increase in signs and symptoms of myasthenia gravis; dizziness, paraesthesia, headache, decrease of tear secretion (ocular dryness), blurred vision, choroidal detachment following filtration surgery; atrioventricular block (complete or lower degree), cardiac failure, arrhythmia, palpitation, cardiac arrest, chest pain, respiratory failure, dyspnoea, alopecia, psoriasiform-like lesions or exacerbation of psoriasis; arthropathy, sexual dysfunction, syndrome of Peyronie.

    The following ADRs have been reported, but a causal relationship to timolol maleate has not been established: aphakic cystoid macular oedema, nasal congestion, anorexia, CNS effects (including confusion, hallucinations, anxiety, disorientation, nervousness, somnolence, and other psychiatric disturbances), hypertension and retroperitoneal fibrosis. The ADRs seen with oral timolol maleate may occur with topical use of Nyolol®.

  • Triamcinolone acetonide (Nasacort® AQ, sanofi-aventis) Warnings: The long-term effects of reduction in growth velocity associated with nasal corticosteroids, including the impact on final adult height are unknown. Glaucoma and/or cataracts have been reported in patients receiving nasal corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma and/or cataracts.

    New ADRs: Flu syndrome, hypersensitivity (including rash, urticaria, pruritus and facial oedema), insomnia, dizziness, alterations of taste and smell; glaucoma, cataract, increased ocular pressure, bronchitis, nasal septum perforations, nasal irritation, dry mucous membrane, dyspnoea, dyspepsia, tooth disorder, nausea, fatigue, decreased blood cortisol.

  • Zanamivir (Relenza®, GSK) Special warnings & precautions: Relenza® inhalation powder must not be made into an extemporaneous solution for administration by nebulisation or mechanical ventilation. There have been reports of hospitalised patients with influenza who received a solution made with Relenza® inhalation powder administered by nebulisation or mechanical ventilation, including a fatal case where it was reported that the lactose in this formulation obstructed the proper functioning of the equipment. Relenza® inhalation powder must only be administered using the device provided.

    New ADRs reported post-market: Anaphylactic and anaphylactoid reactions.

    Vasovagal-like reactions have been reported post-market in patients with influenza symptoms, such as fever and dehydration, shortly following inhalation of Relenza®.

  • Ziprasidone (Zeldox®, Pfizer) Special warnings & precautions: Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with ziprasidone such that preventive measures can be undertaken.

    Pregnancy: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/ or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

March 2011

  • Aripiprazole (Abilify®, Bristol-Myers Squibb) Pregnancy: Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

  • Clobetasol (Lobesol®, Sunward) Precautions: Topically applied corticosteroids can be absorbed in sufficient amount to produce systemic effect. Therefore, patients receiving a large dose of a potent topical steroid applied to a large surface area or under an occlusive dressings should be evaluated periodically for evidence of HPA (hypothalamic-pituitary-adrenal) axis suppression by using the urinary free cortisol and ACTH (adrenocorticotropic hormone) stimulation tests. If HPA axis suppression is noted an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid.

    Recovery of HPA axis function is generally prompt and complete upon discontinuation of the drug. Infrequently, signs and symptoms of steroid withdrawal may occur, requiring supplemental systemic corticosteroids.

    In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favourable response does not occur promptly, the corticosteroids should be discontinued until the infection has been adequately controlled.

    New ADRs: Allergic contact dermatitis, maceration of the skin, secondary infection.

  • Diphenhydramine, ephedrine (Diprodin® elixir, Kotra Pharma) Precaution: Diprodin® elixir is not recommended for children below 2 years old. To be used with caution in children between 2 to 6 years old.
  • Goserelin (Zoladex®, AstraZeneca) New ADRs: Cardiac failure, myocardial infarction, anaphylactic reaction, pituitary tumour, psychotic disorder, vulvovaginal dryness, tumour flare, tumour pain.

    Cardiac failure and myocardial infarction have been observed in a pharmaco-epidemiology study of LHRH (luteinizing hormone-releasing hormone) agonists used in the treatment of prostate cancer. The risk appears to be increased when used in combination with anti-androgens.

  • Hepatitis B vaccine (HBvaxPRO®, MSD) Precautions: Use caution when vaccinating latex-sensitive individuals since the vial stopper and the syringe plunger stopper and tip cap contain dry natural latex rubber that may cause allergic reactions.

  • Human Immunoglobulin (Pentaglobin®, Eshcol) Special precautions: There is clinical evidence of an association between intravenous immunoglobulin (IVIg) administration and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolaemic patients, patients with disease which increase blood viscosity).

    While reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain sucrose may be considered.

    In patients at risk for acute renal failure or thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable.

    There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

    Undesirable effects: Thromboembolic reactions such as myocardial infarctions, stroke, pulmonary embolism, deep vein thromboses, have been observed very rarely.
  • Imatinib (Glivec®, Novartis) Special warnings & precautions: There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib. The long term effects of prolonged treatment with imatinib on growth in children are unknown. Therefore, close monitoring of growth in children under imatinib treatment is recommended.

    Interactions: A non randomized, open-label study was conducted to investigate the effects of Glivec® at steady state on the pharmacokinetics of paracetamol in patients with newly diagnosed, previously untreated chronic myeloid leukaemia (CML) in chronic phase. Co-administration of Glivec® (400 mg/day for eight days) with paracetamol (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of paracetamol. Glivec® pharmacokinetics were not altered in the presence of paracetamol.

    New ADRs reported post-market: Growth retardation in children, tumour lysis syndrome.

  • Indinavir (Crixivan®, MSD) Contraindications: Indinavir should not be administered concurrently with medicinal products with narrow therapeutic windows and which are substrates of CYP3A4.

  • Isoflurane (Forane®, Abbott) Precautions: It has been reported that previous exposure to halogenated hydrocarbon anaesthetics, especially if the interval is less than 3 months, may increase the potential for hepatic injury.

    Isoflurane has been shown to have a possible anaesthetic-related foetotoxic effect in mice when given in doses six times the human dose.

    Safety in pregnancy has not been established. Hence isoflurane should not be administered to pregnant women unless clearly indicated.

    Isoflurane may be used in neonates and infants under two years of age with an acceptable margin of efficiency and safety.

    It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isoflurane is administered to a nursing woman.

    Adverse reactions: Rare reports of hypersensitivity (including dermatitis contact, rash, dyspnoea, wheezing, chest discomfort, swelling face, or anaphylactic reaction) have been received, especially in association with long-term occupational exposure to inhaled anaesthetic agents, including isoflurane. These reactions have been confirmed by clinical testing (e.g. methacholine challenge). The etiology of anaphylactic reactions experienced during inhalational anaesthetic exposure is, however, unclear because of the exposure to multiple concomitant drugs, many of which are known to cause such reactions.

  • Laropiprant, niacin ER (Tredaptive®, MSD) Interaction: In a clinical study in dyslipidaemic patients receiving both aspirin and clopidogrel, laropiprant induced transient (4 hours post-dose) inhibition of platelet function in vivo (as evaluated by bleeding time and platelet aggregation studies), but had little effect across the dosing interval. Patients receiving Tredaptive® concomitantly with aspirin and clopidogrel should be closely monitored.

    Additional ADRs reported post-market with Tredaptive® or other niacin products (with or without a statin) or during clinical trials with Tredaptive® (<1% of patients) or other niacin products (with or without a statin) include: Anaphylactic shock, vesiculobullous rash.

  • Levobupivacaine (Chirocaine®, Abbott) Contraindications: Levobupivacaine is contraindicated in patients with severe hypotension such as cardiogenic or hypovolaemic shock.

    Warnings & precautions: Cases of severe bradycardia, hypotension and respiratory compromise with cardiac arrest (some of them fatal), have been reported in conjunction with local anaesthetics, including levobupivacaine.

    Levobupivacaine should be used with caution in conditions associated with impaired cardiovascular function.

    There is limited safety experience with levobupivacaine therapy for period exceeding 24 hours. Therefore, use of levobupivacaine is not recommended for more than 24 hours.

    Adverse reactions: There have been reports of prolonged weakness or sensory disturbance, some of which may have been permanent, in association with levobupivacaine therapy. It is difficult to determine whether the long-term effects were the result of medication toxicity or unrecognized trauma during surgery or other mechanical factors, such as catheter insertion and manipulation.

    Rare reports have been received of cauda equine syndrome or signs and symptoms of potential injury to the base of the spinal cord or spinal nerve roots (including lower extremity weakness or paralysis, loss of bowel control and/or bladder control and priapism) associated with bupivacaine or levobupivacaine therapy. However, it cannot be determined whether these events are due to an effect of levobupivacaine, mechanical trauma to the spinal cord or spinal nerve roots, or blood collection at the base of the spine.

    There have also been rare reports of transient Horner's syndrome (ptosis, miosis, enophthalmus, unilateral sweating and/or flushing) in association with use of regional anaesthetics, including levobupivacaine. This event resolves with discontinuation of therapy.

  • Midazolam (Dormicum®, Roche) Precautions: Concomitant use of Dormicum® with alcohol and/or CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Dormicum® possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression.

    Dormicum® should be avoided in patients with a medical history of alcohol or drug abuse.

    The  risk of dependence is greater in patients with a medical history of alcohol and/or drug abuse.

    New ADRs: Bronchospasm, anaphylactic shock, bradycardia.

  • Paricalcitol (Zemplar®, Abbott) Warnings & precautions: Chronic hypercalcaemia can lead to generalized vascular calcification and other soft-tissue calcification.

    Interactions: Digitalis toxicity is potentiated by hypercalcaemia of any cause, so caution should be applied when digitalis is prescribed concomitantly with paricalcitol.

    Prescription-based phosphate or vitamin D-related medicinal products should not be taken concomitantly with paricalcitol due to an increased risk of hypercalcaemia and Ca x P (calcium-phosphorus) product elevation.

    Concomitant administration of high doses of calcium-containing preparations or thiazide diuretics with paricalcitol may increase the risk of hypercalcaemia.

    Magnesium-containing preparations (e.g. antacids) should not be taken concomitantly with vitamin D preparations, because hypermagnesaemia may occur.

    Aluminum-containing preparations (e.g., antacids, phosphate-binders) should not be administered chronically with Vitamin D medicinal products, as increased blood levels of aluminum and aluminum bone toxicity may occur.

    New ADRs include: Prolonged bleeding time, abnormal laboratory test, cardiac arrest, atrial flutter, anaemia, leukopenia, lymphadenopathy, dysgeusia, coma, cerebrovascular accident, transient ischaemic attack, syncope, myoclonus, hypoaesthesia, paraesthesia, glaucoma, pulmonary oedema, asthma, dyspnoea, epistaxis, rectal haemorrhage, gastrointestinal haemorrhage, colitis, bullous dermatitis, alopecia, hyperhidrosis, arthralgia, myalgia, hypoparathyroidism, hypercalcaemia, hyperphosphataemia, hypocalcaemia, infection, pharyngitis, influenza, breast cancer, hypotension, gait disturbance, aggravated condition, erectile dysfunction, confusional state, delirium, depersonalization.

    Approximately 600 patients were treated with Zemplar® in Phase II/III/IV clinical trials. Overall, 6% of the Zemplar® treated patients reported adverse reactions.

    The most common adverse reaction associated with Zemplar® therapy was hypercalcaemia, occurring in 4.7% of patients. Hypercalcaemia is dependent on the level of parathyroid hormone (PTH) oversuppression and can be minimised by proper dose titration.

  • Propylthiouracil (Propylthiouracil®, DHA) Warnings & precautions: Severe liver injury and acute liver failure, in some cases fatal, have been reported in patients treated with propylthiouracil. These reports of hepatic reactions include cases requiring liver transplantation in adult and paediatric patients.

  • Rotavirus vaccine (Rotarix®, GSK) Contraindications: Subjects with Severe Combined Immunodeficiency (SCID) disorder.

    Warnings & precautions: The risk of intussusception has been evaluated in a large safety trial (including 63,225 infants) conducted in Latin America and Finland. No increased risk of intussusception was observed in this clinical trial following administration of Rotarix® when compared with placebo.

    However, post-marketing safety data indicate a possible increased risk of intussusception in the 31-day period following the administration of the first dose of Rotarix®.

    Therefore, as a precaution, healthcare professionals should follow-up on any symptoms indicative of intussusception (severe abdominal pain, persistent vomiting, bloody stools, abdominal bloating and/or high fever). Parents/guardians should be advised to promptly report such symptoms.

    Administration of Rotarix® in immunosuppressed infants, including infants on immunosuppressive therapy, should be based on careful consideration of potential benefits and risks.

    Excretion of the vaccine virus in the stools is known to occur after vaccination and lasts for 10 days on average with peak excretion around the 7th day. In clinical trials, cases of transmission of excreted vaccine virus to seronegative contacts of vaccinees have been observed without causing any clinical symptoms. Rotarix® should be administered with caution to individuals with immunodeficient close contacts, such as individuals with malignancies, or who are otherwise immunocompromised or receiving immunosuppressive therapy. Contacts of recent vaccinees should be advised to observe careful hygiene (including washing their hands) when changing children's nappies.

    New ADRs: Cough, runny nose.

    New ADRs reported post-market: Intussusception, haematochezia, gastroenteritis with vaccine viral shedding in infants with Severe Combined Immunodeficiency (SCID) disorder.

    Preliminary data from a large post-marketing epidemiological safety study in Mexico indicate a possible increased risk of intussusception in the 31-day period following the first dose. Spontaneous reports of intussusception have been received mostly within 7 days after the first dose. These observations are limited to the first dose and not seen following administration of the second dose. Whether Rotarix® affects the overall incidence of intussusception has not been established.

    In a clinical study, 1009 preterm infants were administered Rotarix® lyophilised formulation or placebo (198 were 27-30 weeks gestational age and 801 were 31-36 weeks gestational age). The first dose was administered from 6 weeks after birth. Serious adverse events were observed in 5.1% of recipients of Rotarix® as compared to 6.8% of placebo recipients. Similar rates of other adverse events were observed in Rotarix® and placebo recipients. No cases of intussusception were reported.
  • Somatropin (Norditropin® Nordilet®, novo nordisk) Special warnings & precautions: Do not use Norditropin® NordiLet® if the growth hormone solution in the pre-filled pen does not appear water–clear and colourless. Check this by turning the pen upside down once or twice. To make sure you get the proper dose and do not inject air, check the flow (called ‘priming' the pen) before the first injection from a new Norditropin® NordiLet® pen. Do not use the pen if a drop of growth hormone solution does not appear at the needle tip. 

  • Venlafaxine (Efexor® XR, Pfizer) Special warnings: As with other serotonergic agents, the development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions may occur with venlafaxine treatment, particularly with concomitant use of other serotonergic drugs (including SSRIs, SNRIs and triptans), with drugs that impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome synptoms may include mental status changes (e.g. agitation, hallucinations and coma), autonomic instability (e.g. tachycardia, labile blood pressure and hyperthermia), neuromuscular aberrations (eg. Hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g. nausea, vomiting and diarrhoea). Serotonin syndrome, in its most severe form, can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.

    If concomitant treatment with venlafaxine and other agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment inititation and dose increases.

    The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.

February 2011

  • Agomelatine (Valdoxan®, Servier) New ADRs: Mania/ hypomania (these symptoms may also be due to the underlying disease) and related symptoms (as irritability and restlessness); pruritus.

  • Alendronate & Alendronate, colecalciferol (Fosamax® & Fosamax Plus®, MSD) Indication: The optimal duration of use of bisphosphonates for the treatment of osteoporosis has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.

  • Cyanocobalamin, pyridoxine, thiamine (Neurobion® injection, Merck) Warnings & precautions: Due to the content of benzyl alcohol, toxic or anaphylactoid reactions may occur in children below 3 years of age.

    In the literature neuropathies are described under long term intake (6-12 months) of more than 50 mg mean daily dose of vitamin B6. Therefore, under long-term treatment regular monitoring is recommended.

    Interactions: The efficacy of vitamin B6 (pyridoxine) may be decreased by pyridoxine-antagonists e.g. isoniazid (INH), cycloserin, penicillamin, hydralazine.

    In long-term use, the blood level of thiamine may be reduced by loop diuretics e.g. furosemide.

    New ADRs: Nausea, vomiting, diarrhoea, abdominal pain, injection site reactions.

  • Dactinomycin (Lyovac Cosmegen®, Invida) New ADRs: Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

  • Filgrastim (Neupogen® inj, Roche) Undesirable effects: Events of pseudogout have been reported post-market in patients with cancer treated with filgrastim.

  • Glimepiride (Amaryl®, sanofi-aventis) Special warnings & precautions: Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency and a non-sulfonylurea alternative should be considered.

    Interaction: Potentiation of the blood-sugar-lowering effect and, thus, in some instances hypoglycaemia may occur when clarithromycin is taken.

    Special populations: There is no data available on the use of glimepiride in patients under 8 years of age. For children aged 8 to 17 years, there is limited data on glimepiride as monotherapy.

    Available data on safety and efficacy is insufficient in the paediatric population and therefore such use is not recommended.

  • Ibandronic acid (Bondronat®, Roche) Undesirable effects: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been infrequent. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

    Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with bisphosphonates, including ibandronic acid. In some cases, these events did not resolve until the bisphosphonate was discontinued.

    Stomatitis has been reported in patients receiving bisphosphonates.

  • Interferon alfa (Roferon®-A, Roche) Special warnings & precautions: As with other alpha interferons, graft rejections have been reported in patients taking Roferon®-A.

    ndesirable effects: Rarely, alpha interferons including Roferon®-A, used in combination with ribavirin, may be associated with pancytopenia, and very rarely, aplastic anaemia has been reported.

  • Metformin, rosiglitazone (Avandamet®, GSK) Contraindications:
    - Patients with New York Heart Association (NYHA) Class I to IV heart failure.

    - Patients experiencing acute coronary syndrome (ACS) (unstable, angina, non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI)).

    - Patients with ischaemic heart disease.

    Warnings & precautions: While the data on the cardiovascular ischaemic risks of rosiglitazone are not definitive, a possible increased risk of myocardial ischaemic events cannot be ruled out. Therefore, Avandia® is not recommended in patients who have cardiovascular disease or are at risk for cardiovascular disease. Avandamet® is contraindicated in patients with known ischaemic heart disease. There is limited clinical trial data in patients with peripheral arterial disease, therefore, as a precaution, Avandamet® is not recommended in patients with peripheral arterial disease.

    Thiazolinediones or other oral antidiabetic agents have not yet been shown to have beneficial effects on macrovascular risks in patients with type 2 diabetes mellitus.
  • Nicotinic acid (Niaspan®, Abbott) Warnings & precautions: Elevated liver transaminases have been observed with Niaspan® therapy, elevations in transaminases did not appear to be related to treatment duration; elevations in aspartate aminotransferase (AST) levels did not appear to be dose related.

    The risk for myopathy and rhabdomyolysis are increased when lovastatin or simvastatin are co-administered with Niaspan®, particularly in elderly patients and patients with diabetes, renal failure, or uncontrolled hypothyroidism.

    Niaspan® treatment can increase fasting blood glucose. Frequent monitoring of blood glucose should be performed to ascertain that the drug is producing no adverse effects.

    Therapy must be initiated at 500 mg at bedtime in order to reduce the incidence and severity of side effects which may occur during early therapy.

    The daily maintenance dosage should not be increased by more than 500 mg in any 4-week period.

    Doses greater than 2000 mg daily are not recommended. Women may respond at lower Niaspan® extended release doses than men.

    Single-dose bioavailability studies have demonstrated that two of the 500 mg and one of the 1000 mg tablet strengths are interchangeable but three of the 500 mg and two of the 750 mg tablet strengths are not interchangeable.

    Tolerance to flushing of the skin develops rapidly over the course of several weeks. Flushing, pruritus, and gastrointestinal distress are also greatly reduced by slowly increasing the dose of nicotinic acid and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of nicotinic acid extended release ingestion.

    Equivalent doses of nicotinic acid extended release should not be substituted for sustained-release (modified-release, timed-release) nicotinic preparations or immediate-release (crystalline) nicotinic acid.

    Patients already receiving a stable dose of lovastatin or simvastatin who require further TG-lowering or HDL-raising, may receive concomitant dosage titration with Niaspan®. Combination therapy with Niaspan® and lovastatin or Niaspan® and simvastatin should not exceed doses of 2000 mg Niaspan® and 40 mg lovastatin or simvastatin daily.

    Data from clinical trials suggests that women have a greater hypolipidaemic response than men at equivalent doses of Niaspan®.

    Interactions: An in vitro study results suggest that the bile acid-binding resins have high nicotinic acid binding capacity. Therefore, 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of Niaspan®.

    Combination of nicotinic acid with HMG-CoA reductase inhibitors may increase the risk for myopathy and rhabdomyolysis. The prescribing information of the HMG-CoA reductase inhibitor should also be consulted.

    Concomitant aspirin may decrease the metabolic clearance of nicotinic acid. The clinical relevance of this finding is unclear.

    Vitamins or other nutritional supplements containing large doses of nicotinic acid or related compounds such as nicotinamide may potentiate the adverse effects of Niaspan®.

    New ADRs: Flatulence, eructation, feeling hot, bullous dermatitis, muscle spasm, muscular weakness, erythema.

    New ADRs reported post-market: Burning sensation, skin burning sensation, blurred vision, hepatitis, skin discolouration.

    Spontaneous reports suggest that in rare cases, flushing may be more severe and accompanied by symptoms which include burning sensation, skin burning sensation, which in rare cases may lead to syncope.
  • Nilotinib (Tasigna®, Novartis) Interactions: For patients who are unable to swallow capsules, the content of each capsule may be dispersed in one teaspoon of applesauce (pureed apple) and should be taken immediately. Not more than one teaspoon of applesauce and no food other than applesauce must be used.

    New ADRs: Pain in extremity, upper respiratory tract infection, disturbance in attention, tinnitus, atrioventricular block, tachycardia, wheezing, cholestasis, dermatitis, drug eruption, palmar-plantar erythrodysaesthesia syndrome, flank pain, musculoskeletal stiffness, neck pain, back pain.
  • Paclitaxel (Taxol®, Bristol-Myers Squibb) New ADR reported post-market: Scleroderma.

  • Pegfilgrastim (Neulastim®, Roche) New ADRs reported post-market: Erythema, flushing.

    Rare cases of acute febrile dermatosis (Sweet's syndrome) have been reported.

  • Peginterferon alfa-2a (Pegasys®, Roche) Contraindication: Initiation of Pegasys® is contraindicated in HIV-HCV patients with cirrhosis and a Child-Pugh score ≥ 6 except if only due to indirect hyperbilirubinaemia caused by drugs such as atazanavir and indinavir.

    Special warnings & precautions: Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of ribavirin and azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone.

    The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinaemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Pegasys® should be discontinued immediately in patients with hepatic decompensation.

    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®.

    Interactions: Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase,  may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine. The use of peginterferon alfa-2a and ribavirin concomitantly with azathioprine should be avoided. In individual cases where the benefit of administering ribavirin concomitantly with azathioprine warrants the potential risk, it is recommended that close haematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these drugs should be stopped.

    New ADRs reported post-market: Pure red cell aplasia (PRCA) and homicidal ideation.

  • Pemetrexed (Alimta®, Eli Lilly) Special warnings & precautions: The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. A phase 2 study of pemetrexed in 31 solid tumour patients with stable third space fluid demonstrated no difference in pemetrexed dose-normalized plasma concentrations or clearance compared to patients without third space fluid collections. Thus, drainage of third space fluid collection prior to pemetrexed treatment should be considered, but may not be necessary.

    Interactions: In Vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic anion transporter 3).

    Although ibuprofen, diclofenac, naproxen & celecoxib in moderate doses can be administered with pemetrexed in patients with normal renal function (creatinine clearance ≥80 ml/min), caution should be used when administering these NSAIDS concurrently with pemetrexed to patients with renal insufficiency (creatinine clearance 45 - 79 ml/min).

  • Piribedil (Trivastal® retard, Servier) Warnings & precautions: Cases of pathological gambling (compulsive gambling), hypersexuality and increased libido have been reported in patients with Parkinson's disease treated with dopamine agonists, and with Trivastal® in particular. These cases have been seen mainly in patients receiving high doses and were generally reversible following dosage reduction or discontinuation of the treatment with dopamine agonists.
  • Rosiglitazone (Avandia®, GSK) Contraindications:
    - Patients with New York Heart Association (NYHA) Class I to IV heart failure.

    - Patients experiencing acute coronary syndrome (ACS) (unstable, angina, non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI)).

    - Patients with ischaemic heart disease.

    Warnings & precautions: While the data on the cardiovascular ischaemic risks of rosiglitazone are not definitive, a possible increased risk of myocardial ischaemic events cannot be ruled out. Therefore, Avandia® is not recommended in patients who have cardiovascular disease or are at risk for cardiovascular disease. Avandia® is contraindicated in patients with known ischaemic heart disease. There is limited clinical trial data in patients with peripheral arterial disease, therefore, as a precaution, Avandia® is not recommended in patients with peripheral arterial disease.

    Thiazolinediones or other oral antidiabetic agents have not yet been shown to have beneficial effects on macrovascular risks in patients with type 2 diabetes mellitus.

  • Testosterone (Nebido® solution, Bayer) Special warnings & precautions: Cases of benign and malignant liver tumours have been reported in users of hormonal substances such as androgen compounds. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur in men using Nebido®, a liver tumour should be included in the differential-diagnostic considerations.

    Caution should be exercised in patients predisposed to oedema, as treatment with androgens may result in increased sodium retention.

    Clinical trials with Nebido® in children or adolescents under the age of 18 have so far not been conducted.

    In children testosterone, besides masculinization, can cause accelerated growth and bone maturation and premature epiphyseal closure, thereby reducing final height. The appearance of common acne has to be expected.

    Special populations: Limited data does not suggest the need for a dosage adjustment in elderly patients.

    No formal studies have been performed in patients with hepatic impairment & renal impairment. The use of Nebido® is contraindicated in men with past or present liver tumours.

  • Varicella virus vaccine (Varivax®, MSD) Precautions: Post-marketing experience suggests that transmission of vaccine virus may occur rarely from healthy vaccinees who develop a varicella-like rash to healthy susceptible contacts. Transmission of vaccine virus from a mother who did not develop a varicella-like rash to her newborn infant has also been reported.

    Therefore, vaccine recipients should attempt to avoid, whenever possible, close association with susceptible high-risk individuals for up to six weeks. In circumstances where contact with high-risk individuals is unavoidable, the potential risk of transmission of vaccine virus should be weighed against the risk of acquiring and transmitting wild-type varicella virus. Susceptible high-risk individuals include all newborn infants born at <28 weeks gestation regardless of maternal varicella immunity.

    New ADR reported post-market: Aplastic anaemia.

January 2011

  • Acetylcysteine, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine (Aminoplasmal® infusion, B. Braun) Contraindications:
    - Severe circulation disorders with vital risk (e.g. shock)

    - Hypoxia

    - Severe renal insufficiency without access to haemofiltration or haemodialysis

    - Decompensated cardiac insufficiency

    - Acute pulmonary oedema

    Special warnings & precautions: Aminoplasmal® should only be administered after careful benefit-risk assessment in the presence of disorders of amino acid metabolism of other origin (apart from congenital abnormalities of amino acid metabolism).

    Care should be exercised in the administration of large volume infusion fluids to patients with cardiac insufficiency.

    In patients with hepatic and renal insufficiency, the dose must be adjusted according to individual requirements.

    Hypotonic dehydration should be corrected by adequate supply of fluid and electrolytes prior to parenteral nutrition.

    In cases of hypokalaemia or hyponatraemia adequate amounts of potassium or sodium should be supplied.

    Caution should be exercised in patients with increased serum osmolarity.

    Serum electrolytes, blood glucose, fluid balance, acid-base balance and renal function (blood urea nitrogen, creatinine) should be monitored regularly.

    Monitoring should also include serum protein and liver function tests.

    The site of infusion should be checked daily for signs of inflammation or infection.

    Aminoplasmal®– 15 % contains 5.3 mmol (121 mg) of sodium per litre. This is to be taken into consideration by patients on a controlled sodium diet.

    ADRs that can occur as a result of parenteral nutrition, particularly at the beginning of the treatment: Nausea, vomiting, headache, shivering, fever.

    Pregnancy & lactation: Studies in pregnant or breastfeeding women have not been conducted with this medicinal product. There is no preclinical data regarding the administration of Aminoplasmal® during pregnancy. Aminoplasmal® should therefore be administered with caution during pregnancy and lactation and only if deemed clearly indicated after assessment of its benefits and possible risks.

  • Aliskiren (Rasilez®, Novartis) Special warnings & precautions: Concomitant use of aliskiren with ciclosporin or itraconazole, both potent P glycoprotein inhibitors, is not recommended.

    Interaction: In healthy subjects, itraconazole (100 mg) increases AUC and Cmax of aliskiren (150 mg) by 6.5 fold and 5.8 fold, respectively. Therefore, concomitant use of itraconazole with aliskiren is not recommended.

    New ADR reported post-market: Increased blood creatinine.

  • Glibenclamide, metformin (Glucovance®, Merck) Contraindications:
    - Renal disease or renal dysfunction (CrCl < 60ml/min) which may result from conditions e.g. intravascular administration of iodinated contrast materials.

    - Acute or chronic diseases which may cause tissue hypoxia e.g. respiratory failure.

    - Type I diabetes.

    - Major surgery.

    - Hepatic insufficiency, acute alcohol intoxication, alcoholism.

    - Porphyria.

    - In association with miconazole.

    - Lactation.

    Precautions: The careful selection of patients and dosage and adequate instructions for the patient are important to reduce the risk of hypoglycaemic episodes. If the patient encounters repeated episodes of hypoglycaemia, which are either severe or associated with unawareness of the situation, antidiabetic treatment options other than Glucovance® should be taken into consideration.

    Moderate hypoglycaemic symptoms without loss of consciousness or neurological manifestations should be corrected by the immediate intake of sugar. An adjustment to the dosage and/or changes to meal patterns should be ensured. Severe hypoglycaemic reactions with coma, seizures or other neurological signs are also possible and constitute a medical emergency requiring immediate treatment with intravenous glucose once the cause is diagnosed or suspected, prior to prompt hospitalisation of the patient.

    Because Glucovance® contains metformin, Glucovance® must be discontinued 48 hours before elective major surgery, and may not be reinstituted earlier than 48 hours afterwards and only after renal function has been re-evaluated and found to be normal.

    In case of surgery or any other cause of diabetic decompensation, temporary insulin therapy should be envisaged instead of this treatment.

    Because this medicinal product contains lactose, it is contraindicated in case of congenital galactosaemia, glucose and galactose malabsorption syndrome or in case of lactase deficiency.

    Dosage of Glucovance® must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glibenclamide/2000 mg metformin. Any intake must be followed by a meal with a sufficiently high carbohydrate content to prevent the onset of hypoglycaemic episodes.

    Glucovance® 5mg/500mg should not be used as initial therapy due to an increased risk of hypoglycaemia.

    For patients previously treated with combination therapy of glibenclamide (or another sulphonylurea) plus metformin, if switched to Glucovance®, the starting dose should not exceed the daily dose of glibenclamide (or equivalent dose of another sulphonylurea) and metformin already being taken. Patients should be monitored closely for signs and symptoms of hypoglycaemia following such a switch and the dose of Glucovance® should be titrated accordingly to achieve adequate control of blood glucose.

    Interactions: Increase in the hypoglycaemic effect with possible onset of hypoglycaemic manifestations, or even coma has been reported when miconazole (systemic route, oromucosal gel) is administered concomitantly with glibenclamide.

    Depending on the renal function, Glucovance® must be discontinued before the test or at the time of the test with iodinated contrast materials due to interaction with metformin.

    Antabuse effect (intolerance to alcohol) has been noted for chlorpropamide, glibenclamide, glipizide, tolbutamide.

    Increase of the hypoglycaemic reaction (inhibition of compensation reactions), which may facilitate the onset of a hypoglycaemic coma, has been reported when alcohol is taken with sulphonylurea(s). Avoid consumption of alcohol and alcohol-containing medications.

    There is an increased risk of hepatotoxicity if bosentan is given with glibenclamide and it is recommended that such use to be avoided; the hypoglycaemic effect of glibenclamide may also be reduced.

    If the combination of danazol and antidiabetic agent(s) cannot be avoided, warn the patient and step up self-monitoring of blood glucose. Dosage of the antidiabetic during treatment with danazol and after its withdrawal may need to be adjusted.

    Increased risk of lactic acidosis during alcoholic intoxication, particularly in cases of fasting or malnutrition and hepatocellular failure, has been reported when metformin is administered with alcohol. Avoid drinking alcoholic beverages and taking drugs that contain alcohol.

    Lactic acidosis due to metformin triggered by an functional renal insufficiency, related to diuretics and more particularly to loop diuretics, has been reported.

    All beta-blockers, clonidine, reserpine, guanethidine and sympathomimetics mask some of the symptoms of hypoglycaemia: palpitations and tachycardia.

    Most non-cardioselective beta-blockers increase the incidence and severity of hypoglycaemia. Warn the patient and step up blood glucose self-monitoring, especially at the start of treatment when glibenclamide is administered concomitantly.

    Increase in the half-life of sulphonylurea with possible onset of hypoglycaemic manifestations has been reported with fluconazole. Warn the patient and step up self-monitoring of blood glucose, and possibly adjust the dosage of the antidiabetic during treatment with fluconazole and after its withdrawal.

    Reduction in antidiuretic activity has been reported when desmopressin is administered concomitantly with glibenclamide.

    Special populations: Glucovance® is not recommended for use during pregnancy or for use in children.

    The initial and maintenance dosing of Glucovance® should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function.

    Pregnancy and lactation: When uncontrolled, diabetes (gestational or permanent) gives rise to an increase in congenital abnormalities and perinatal mortality.

    Diabetes must be controlled as far as possible during the period of conception in order to reduce the risk of congenital abnormalities.

    Adequate blood glucose control allows pregnancy to proceed normally in this category of patients. Glucovance® must not be used for the treatment of diabetes during pregnancy.

    It is imperative that insulin be used to achieve adequate blood glucose control. It is recommended that the patient be transferred from oral antidiabetic therapy to insulin as soon as she plans to become pregnant or if pregnancy is exposed to this medicinal product. Neonatal blood glucose monitoring is recommended.

    In humans, in the absence of data concerning passage of Glucovance® into breast milk, and in view of the risk of neonatal hypoglycaemia, this medicinal product is contraindicated in the event of breastfeeding.

  • Glyceryl trinitrate (Angised®, GSK) Contraindications:
    - In patients with possible increased intracranial pressure (e.g. cerebral haemorrhage or head trauma).

    - In patients taking phosphodiesterase type 5 inhibitors (e.g. vardenafil, tadalafil).

    - In patients who are hypersensitive to other nitro compounds.

    Warnings & precautions: Angised® should be used with caution in patients in whom adequate preload is important for maintaining cardiac output (e.g. acute circulatory shock including hypovolaemic shock or cardiogenic shock with inadequate diastolic filling pressures, severe mitral stenosis, pericardial tamponade, constrictive pericarditis, orthostatic dysfunction) because administration of a vasodilator in these patients may worsen clinical status.

    Interactions: Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, phosphodiesterase type 5 inhibitors (e.g. vardenafil and tadalafil) have been shown to potentiate the hypotensive effects of nitrates, and coadministration with Angised® is therefore contraindicated.

    New ADRs: Cerebral ischaemia, syncope, drowsiness, enhanced angina pectoris symptoms, circulatory collapse, nausea, heartburn, exfoliative dermatitis, asthenia.

    Lightheadedness and hypotension may be exacerbated in an upright or standing position.

    During treatment with Angised®, temporary hypoxaemia may occur due to a relative redistribution of the blood flow in hypoventilated alveolar areas.

    Pregnancy & lactation: Animal studies did not indicate harmful effects with respect to pregnancy, embryofoetal development, parturition or postnatal development. However, the relevance of these animal findings to man is unknown.

    It is unknown if Angised® or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue/abstain from breastfeeding or to discontinue/abstain from Angised® therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

  • Granisetron (Kytril®, Roche) Precautions: As with other 5-HT3 antagonists, cases of ECG modifications including QT prolongation have been reported with Kytril®. These ECG changes with Kytril® were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. However, in patients with pre-existing arrhythmias or cardiac conduction disorders, this might lead to clinical consequences. Therefore, caution should be exercised in patients with cardiac comorbidities, on cardio-toxic chemotherapy and/or with concomitant electrolyte abnormalities.

    Interactions: In patients concurrently treated with drugs known to prolong QT interval and/or are arrhythmogenic, this may lead to clinical consequences.

  • Hydromorphone (Jurnista®, J & J) Jurnista® should not be taken more than once every 24 hours.

  • Influenza vaccine (Fluarix®, GSK) Adverse reactions: During post-marketing surveillance, spontaneous reports of Guillain-Barré syndrome have been received following vaccination with Fluarix®; however, a causal association between vaccination and Guillain-Barré syndrome has not been established.

  • Insulin lispro, insulin lispro protamine (Humalog® Mix, Eli Lilly) Interaction: Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, e.g. angiotensin II receptor blockers.
  • Ipratropium, fenoterol (Duovent®, Boehringer Ingelheim) Special warnings & precautions: In patients with bronchial asthma, Duovent® 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.

    Duovent® 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 Duovent® 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).

    New ADRs: Dysphonia, mental disorder, conjunctival hyperaemia, halo vision, dry throat, stomatitis, glossitis, mouth oedema, muscular weakness.
  • Ipratropium, salbutamol (Combivent®, Boehringer Ingelheim) Special warnings & precautions: Care must be taken not to allow the solution or mist to enter into the eyes. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.

    Cardiovascular effects may be seen with sympathomimetic drugs, including Combivent®. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with salbutamol. Patients with underlying severe heart disease (e.g. ischaemic heart disease, tachyarrhythmia or severe heart failure) who are receiving salbutamol for respiratory disease, should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease. Attention should be paid to assessment of symptoms as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin.

    The use of Combivent® may lead to positive results with regards to salbutamol in tests for nonclinical substance abuse, e.g. in the context of athletic performance enhancement (doping).

    Because of insufficient information in children Combivent® is not indicated for paediatric patients.

    Combivent® has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations.

    Patients should be advised to consult a doctor or the nearest hospital immediately in the case of acute or rapidly worsening dyspnoea (difficulty in breathing) if additional inhalations of Combivent® do not produce an adequate improvement.

    In asthma, concomitant anti-inflammatory therapy should be considered.

    New ADRs: Accommodation disorder, conjunctival hyperaemia, halo vision, supraventricular tachycardia, dry throat, paradoxical bronchospasm, stomatitis.
  • Ketotifen (Zaditen® & Zaditen® SRO, Novartis) Contraindications: Epilepsy or history of seizures.

    New ADRs reported post-market: Convulsion, somnolence, headache, vomiting, nausea, rash, urticaria.

  • Lactulose (Dhactulose®, DHA) Contraindication: Galactosaemia.

    Interactions: Because of the mode of action of lactulose, in which the colonic pH is lowered, the action of substances with release dependent on pH (e.g. 5-aminosalicylic acid formulations) may be reduced.

  • Lamotrigine (Lamitor®, Apotheca) Warnings: Therapy with lamotrigine 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 lamotrigine 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 lamotrigine. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following reinitiation of treatment) that were frequently more severe. Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases. Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized 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.

  • Measles, mumps, rubella & varicella vaccine live (Priorix-Tetra®, GSK) Special warnings & precautions: 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.

  • Nifedipine (Adalat® LA, Bayer) New ADRs reported post-market: Agranulocytosis, leukopenia, hyperglycaemia, hypoaesthesia, somnolence, eye pain, chest pain (angina pectoris), gastrooesophageal sphincter insufficiency, jaundice, toxic epidermal necrolysis, photosensitivity allergic reaction, palpable purpura, arthralgia, myalgia.

    Special populations: The safety and efficacy of Adalat® LA in children below 18 years has not been established.

    The pharmacokinetics of Adalat® LA are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.

  • Povidone iodine (Betadine® vaginal douche, Mundipharma) Contraindications:
    - Allergy to iodine or povidone.

    - Overactive thyroid gland (hyperthyroidism) or any thyroid diseases.

    - Before and after a specific medical treatment involving the use of radioactive iodine.

    New ADRs: Itch, redness, small blisters, drop in blood pressure, difficulty in breathing, swelling of the skin and mucosa.
  • Ranibizumab (Lucentis®, Novartis) Special warnings & precautions: Lucentis® has not been studied in patients with active systemic infections or in patients with concurrent eye conditions such as retinal detachment or macular hole.

    Pregnancy: For ranibizumab no clinical data on exposed pregnancies is available. The potential risk for humans is unknown. Caution should be exercised when prescribing to pregnant women.
  • Ranitidine (Zantac®, GSK) Interactions: Ranitidine has the potential to affect the absorption, metabolism or renal excretion of other drugs. The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of treatment.

    Interactions occur by several mechanisms including:
    1) Inhibition of cytochrome P450-linked mixed function oxygenase system:
    Ranitidine at usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this enzyme system such as diazepam, lidocaine, phenytoin, propranolol and theophylline.

    There have been reports of altered prothrombin time with coumarin anticoagulants (e.g. warfarin). Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine.

    2) Competition for renal tubular secretion:
    Since ranitidine is partially eliminated by the cationic system, it may affect the clearance of other drugs eliminated by this route. High doses of ranitidine (e.g. those used in the treatment of Zollinger-Ellison syndrome) may reduce the excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of these drugs.

    3) Alteration of gastric pH:
    The bioavailability of certain drugs may be affected. This can result in either an increase in absorption (e.g. triazolam, midazolam, glipizide) or a decrease in absorption (e.g. ketoconazole, atazanavir, delaviridine, gefitnib).

    New ADRs: Gynaecomastia and galactorrhoea.

  • Selegiline (Jumex®, sanofi aventis) Interactions: Confusion, hypomania, hallucination and maniac episodes, agitation, myoclonus, hyperreflexia, incoordination, tremor, shaking, seizures, ataxia, diaphoresis, diarrhoea, fever, and hypertension may constitute the symptoms of serotonin syndrome; and due to the risk of its development concomitant administration of selegiline and selective serotonine-reuptake inhibitors is contraindicated.

    New ADR: Hypersexuality.

  • Temozolomide (Temodal®, Schering-Plough) Undesirable effects: Cases of hepatotoxicity including elevations of liver enzymes, hyperbilirubinaemia, cholestasis and hepatitis have been reported post-market.

  • Tocilizumab (Actemra®, Roche) Warnings & precautions: Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab.

    A patient with a previous infusion reaction and premedicated with steroids and antihistamines experienced a fatal anaphylactic reaction during a subsequent treatment with tocilizumab in the post-marketing setting. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of tocilizumab should be stopped immediately and tocilizumab should be permanently discontinued.

  • Topiramate (Topamax®, J & J) Pregnancy: Compared with a reference group not taking antiepileptic drugs, registry data for Topamax® monotherapy showed a higher prevalence of low birth  weight (<2500 grams). A causal relationship has not been established.

  • Varicella-zoster virus vaccine (Zostavax®, MSD) Precautions: Post-marketing experience with varicella vaccines suggests that transmission of vaccine virus may occur rarely from vaccinees who develop a varicella-like rash to susceptible contacts. Transmission of vaccine virus from varicella vaccine recipients who do not develop a varicella like rash has also been reported.

Last updated on 07 Aug 2013 19:27:23
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