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This application is a service of the Singapore Government.

Health Sciences Authority

April 2012

2S/No
Product Name
Active ingredient
1
Fluimucil®
Acetylcysteine
2
Symmetrel®
Amantadine HCL
3
Agrylin®
Anagrelide
4
Equoral®
Ciclosporin
5
Cipram®
Citalopram
6
Ciram®
Citalopram
7
Boostrix™
Diphtheria, tetanus, pertussis toxoids
8
Motilium®, Dompel®, Domperdone®, Dompenyl®, Doridone® Domperidone®
Domperidone
9
Avodart® Dutasteride
10
Syntometrine®
Ergometrine, oxytocin
11
Invanz®
Ertapenem sodium
12
Certican®
Everolimus
13
Diflucan®
Fluconazole
14
DBL™ Fluorouracil
Fluorouracil
15
Flixotide™ Evohaler
Fluticasone propionate
16
Gonal-f™
Follitropin alfa
17
Brufen®
Ibuprofen
18
Extraneal®
Icodextrin
19
Ventavis®
Iloprost trometamol
20
Coralan®
Ivabradine
21
Fosrenol®
Lanthanum
22
Femara®
Letrozole
23
Metoclopramide®
Metoclopramide HCL
24
Metronidazole Fresenius®
Metronidazole
25
Ramezol®
Omeprazole
26
Pamisol™
Pamidronate disodium
27
Dilantin®
Phenytoin sodium
28
Actos®
Pioglitazone
29
Effient®
Prasugrel HCL
30
Sonovue®
Sulfur hexafluoride
31
Dogmatil®
Sulpiride
32 Co-Diovan®
Valsartan, Hydrochlorothiazide
  • Acetylcysteine (Fluimucil®, United Italian) Contraindications: Children under 2 years of age.

    Warnings & precautions: Antitussive drugs should be avoided because they cause accumulation of mucus in the airways.

    Mucolytic agents can induce respiratory obstruction in children under 2 years of age. Due to the physiological characteristics of the airways in this age group, the ability to expectorate may be limited. Therefore, mucolytics should not be used in children under 2 years of age.

    New ADRs include: Anaphylactic shock, severe skin reaction, shortness of breath, increased heart rate, stomatitis, fever, decrease in blood pressure.

  • Amantadine (Symmetrel®, Novartis) Warnings & precautions: Pathological gambling, increased libido and hypersexuality have been reported in patients treated with dopamine agonists for Parkinson's disease, including Symmetrel®, especially at high doses. These are generally reversible upon reduction of the dose or treatment discontinuation.

    Interactions: Concomitant administration of amantadine with fixed dose combination of hydrochlorothiazide and triamterene may reduce the systemic clearance of the drug leading to increased plasma concentrations and toxic effects (confusion, hallucinations, ataxia, myoclonus).

  • Anagrelide (Agrylin®, LF Asia) Interactions: In some essential thrombocythaemiapatients concomitantly treated by acetylsalicylic acid and anagrelide, major haemorrhages occurred.

    The experience in children is limited. Anagrelide should be used in this patient group with caution.

  • Ciclosporin (Equoral®, Dynamed) Contraindications apply to the non-transplant indications: - Kidney failure, except in patients with nephrotic syndrome, in whom disease-related moderate increases in baseline serum creatinine values (max. 200umol/L in adults and max. 140umol/L in children) improve and cautious therapy (max. 2.5mg/kg/day) is thus permitted.

    - History of known or diagnosed malignancy of any kind except premalignant or malignant skin changes.

    Special warnings & precautions: Activation of latent Polyomavirus infections that may lead to Polyomavirus associated nephropathy (PVAN), especially to BK virus nephropathy (BKVN), or to JC virus associated progressive multifocal leukoencephalopathy (PML) have been observed in patients receiving ciclosporin. These conditions are often related to a high total immunosuppressive burden and should be considered in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Serious and/or fatal outcomes have been reported. Effective pre-emptive and therapeutic strategies should be employed particularly in patients on multiple long-term immunosuppressive therapy.

    There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported.

    Ciclosporin may increase blood levels of concomitant medications that are substrates of P-glycoprotein (Pgp) such as aliskiren.

    Patients with abnormal baseline renal function should initially be treated with 2.5 mg/kg per day and must be monitored very carefully.

    Elderly patients should be treated only in the presence of disabling psoriasis, and renal function should be monitored with particular care.

    Interactions: Literature and post-marketing cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported with concomitant administration of ciclosporin with lovastatin, simvastatin, atorvastatin, pravastatin, and rarely, fluvastatin.

    If digoxin or colchicine is used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of digoxin or colchicine, followed by reduction of dosage or its withdrawal.

    New ADR: Migraine.

  • Citalopram (Cipram®, LF Asia) Contraindications: Citalopram should not be given to patients receiving monoamine oxidase inhibitors (MAOIs) (including selegiline in daily doses exceeding 10mg/day). Citalopram should not be given for 14 days after discontinuation of an irreversible MAOI or for the time specified after discontinuation of a reversible MAOI (RIMA) as stated in the prescribing text of the RIMA. MAOIs should not be introduced for 7 days after discontinuation of citalopram.Citalopram is contraindicated in the combination with linezolid unless there are facilities for close observation and monitoring of blood pressure.

    Citalopram is contraindicated in patients with known QT interval prolongation or congenital long QT syndrome.

    Special warnings & precautions: Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported as a rare adverse reaction with the use of selective serotonin reuptake inhibitors (SSRIs) and generally reverses on discontinuation of therapy. Elderly female patients seem to be at higher risk.

    Seizures are a potential risk with antidepressant drugs. Citalopram should be discontinued in any patient who develops seizures. Citalopram should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Citalopram should be discontinued if there is an increase in seizure frequency.

    In patient with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/ or oral hypoglycaemic dosage may need to be adjusted.

    In rare cases, serotonin syndrome has been reported in patients using SSRIs. A combination of symptoms such as agitation, tremor, myoclonus, and hyperthermia may indicate the development of this condition. Treatment with citalopram should be discontinued immediately and symptomatic treatment initiated.

    Citalopram should not be used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol, oxitriptan, and tryptophan.

    There have been reports of cutaneous bleeding time and/or bleeding abnormalities such as ecchymoses, gynaecological haemorrhages, gastrointestinal bleedings, and other cutaneous or mucous bleedings with SSRIs. Caution is advised in patients taking SSRIs, particularly with concomitant use of active substances known to affect platelet function or other active substances that can increase the risk of haemorrhage, as well as in patients with a history of bleeding disorders.

    Citalopram and St. John's Wort preparations should not be taken concomitantly.

    Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.

    Citalopram has been found to cause a dose-dependent prolongation of the QT interval and should not be dosed above 40mg/day. Citalopram should not be used in patients with congenital long QT syndrome. Cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period, predominantly in patients of female gender, with hypokalaemia, or with pre-existing QT prolongation or other cardiac diseases.

    Caution is advised in patients at higher risk of developing prolongation of the QT interval, including those with congestive heart failure, recent acute myocardial infarction or uncompensated heart failure, bradyarrhythmias or a predisposition to hypokalaemia or hypomagnesaemia because of concomitant illness or drugs.

    Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for malignant arrhythmias and should be corrected before treatment with citalopram is started.

    If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.

    ECG monitoring is recommended in patients with congestive heart failure, bradyarrhythmias, or patients on concomitant medications that prolong the QT interval.

    If signs of cardiac arrhythmia occur during treatment with citalopram, the treatment should be withdrawn and an ECG should be performed.

    Dose escalations over 20mg/day in elderly patients (>65 years), patients with hepatic dysfunction, CYP2C19 poor metabolisers or patients taking concomitant cimetidine or another CYP2C19 inhibitor are not recommended.

    Interactions: The simultaneous use of citalopram and MAOIs can result in severe undesirable effects, including the serotonin syndrome.

    Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a MAOI, including the irreversible MAOI selegiline, the reversible MAOI linezolid and moclobemide and in patients who have recently discontinued SSRI and have been started on a MAOI.

    Some cases presented with features resembling serotonin syndrome. Symptoms of an active substance interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.

    A pharmacokinetic/ pharmacodynamic interaction study with concomitantly administered citalopram (20mg daily) and selegiline (10mg daily) (a selective MAO-B inhibitor) demonstrated no clinically relevant interactions. The concomitant use of citalopram and selegiline (in doses above 10mg daily) is not recommended.

    Until further information is available, the simultaneous use of citalopram and 5-HT agonists, such as sumatriptan and other triptans, is not recommended.

    Caution is warranted for patients who are being treated simultaneously with anticoagulants, medicinal products that affect the platelet function, such as non-steroidal anti-inflammtory drugs (NSAIDs), acetylsalicylic acid, dipyridamole, and ticlopidine or other medicines (e.g. atypical antipsychotics, phenothiazines, tricyclic antidepressants) that can increase the risk of haemorrhage.

    SSRIs can lower the seizure threshold. Caution is advised when concomitantly using other medicinal products capable of lowering the seizure threshold (e.g. antidepressants [tricyclics, SSRIs], neuroleptics [phenothiazines, thioxanthenes, and butyrophenones]), mefloquin, bupropion and tramadol).

    In a pharmacokinetic study no effect was demonstrated on either citalopram or imipramine levels, although the level of desipramine, the primary metabolite of imipramine, was increased. When desipramine is combined with citalopram, an increase of the desipramine plasma concentration has been observed. A reduction of the desipramine dose may be needed.

    Experience with citalopram has not revealed any clinically relevant interactions with neuroleptics. However, as with other SSRIs, the possibility of a pharmacodynamic interaction cannot be excluded.

    Pharmacokinetic and pharmacodynamic studies between citalopram and other medicinal products that prolong the QT interval have not been performed. An additive effect of citalopram and these medicinal products cannot be excluded. Therefore, coadministration of citalopram with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotics (e.g. fentiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, anti-malarial treatment particularly halofantrine), certain antihistamines (astemizole, mizolastine) should only be prescribed after careful consideration.

    Caution is advised when administering citalopram in combination with cimetidine. Dose adjustment may be warranted.

    Coadministration of escitalopram (the active enantiomer of citalopram) with omeprazole 30mg once daily (a CYP2C19 inhibitor) resulted in moderate (approximately 50%) increase in the plasma concentrations of escitalopram. Thus, caution should be exercised when used concomitantly with CYP2C19 inhibitors (e.g. omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine). A reduction in the dose of citalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.

    Caution is recommended when metoprolol with citalopram are coadministered. Dose adjustment may be warranted.

    New ADRs include: Hypokalaemia, abnormal liver function test, prolonged ECG QT, ventricular arrhythmia including torsade de pointes.

    Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk bone fractures in patients receiving SSRIs and tricyclic antidepressants (TCAs). The mechanism leading to this risk is unknown.

    Pregnancy & lactation: Published data on pregnant women (more than 2500 exposed outcomes) indicate no malformative feto-/ neonatal toxicity. However, citalopram should not be used during pregnancy unless clearly necessary and only after careful consideration of benefit/ risk.

    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.

    If treatment with citalopram is considered necessary, discontinuation of breastfeeding should be considered.

  • Citalopram (Ciram®, DHA) Contraindications: Citalopram is contraindicated in patients with known QT interval prolongation or congenital long QT syndrome.

    Special warnings & precautions: Citalopram has been found to cause a dose-dependent prolongation of the QT interval and should not be dosed above 40mg/day. Citalopram should not be used in patients with congenital long QT syndrome. Cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period, predominantly in patients of female gender, with hypokalaemia, or with pre-existing QT prolongation or other cardiac diseases.

    Caution is advised in patients at higher risk of developing prolongation of the QT interval, including those with congestive heart failure, recent acute myocardial infarction or uncompensated heart failure, bradyarrhythmias or a predisposition to hypokalaemia or hypomagnesaemia because of concomitant illness or drugs.

    Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for malignant arrhythmias and should be corrected before treatment with citalopram is started.

    If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.

    ECG monitoring is recommended in patients with congestive heart failure, bradyarrhythmias, or patients on concomitant medications that prolong the QT interval.

    If signs of cardiac arrhythmia occur during treatment with citalopram, the treatment should be withdrawn and an ECG should be performed.

    Dose escalations over 20mg/day in elderly patients (>65 years), patients with hepatic dysfunction, CYP2C19 poor metabolisers or patients taking concomitant cimetidine or another CYP2C19 inhibitor are not recommended.

    Interactions: Pharmacokinetic and pharmacodynamic studies between citalopram and other medicinal products that prolong the QT interval have not been performed. An additive effect of citalopram and these medicinal products cannot be excluded. Therefore, coadministration of citalopram with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotics (e.g. fentiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, anti-malarial treatment particularly halofantrine), certain antihistamines (astemizole, mizolastine) should only be prescribed after careful consideration.

    New ADRs: Prolonged ECG QT, ventricular arrhythmia including torsade de pointes.

  • Diphtheria, tetanus, pertussis toxoids (Boostrix™, GSK) Warnings & precautions: Boostrix™ should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects. Firm pressure should be applied to the injection site (without rubbing) for at least two minutes.

    Extremely rare cases of collapse or shock-like state (hypotonic-hyporesponsiveness episode) and convulsions within 2 to 3 days of vaccination have been reported in DTPa and DTPa combination vaccines.

    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.

    As with any vaccine, a protective immune response may not be elicited in all vaccinees.

    New ADRs reported in children from 4 to 9 years of age include: Upper respiratory tract infection, anorexia, conjunctivitis.

    New ADRs reported in adults, adolescents and children from the age of 10 years onwards include: Pharyngitis, syncope, hyperhidrosis, arthralgia, influenza-like illness.

    New ADRs reported post-market include: Convulsions (with or without fever), extensive swelling of the vaccinated limb, asthenia, anaphylactic and anaphylactoid reactions.

    Data on 146 subjects suggest a small increase in local reactogenicity (pain, redness, swelling) with repeated vaccination according to a 0, 1, 6 months schedule in adults (> 40 years of age).

    Subjects fully primed with 4 doses of DTPw followed by a Boostrix™ dose around 10 years of age show an increase of local reactogenicity after an additional Boostrix™ dose administered 10 years later.

    Lactation: The safety of Boostrix™ when administered to breastfeeding women has not been evaluated. It is unknown whether Boostrix™ is excreted in human breast milk. Boostrix™ should only be used during breastfeeding when the possible advantages outweigh the potential risks.

  • Domperidone (Motilium®, J & J; Dompel®, Pharmaforte; Domperdone®, MD Pharmaceuticals; Dompenyl®, Ziwell Medical; Doridone®, DHA; Sam Chun Dang Domperidone®, Zyfas Medical) Special warnings & precautions: Some epidemiological studies showed that domperidone may be associated with an increased risk of serious ventricular arrhythmias or sudden cardiac death. The risk may be higher in patients older than 60 years or at daily doses of more than 30 mg. Therefore, doses above 30mg/day should be used with caution due to potential risk of arrhythmias associated with the higher doses. Domperidone should be used at the lowest effective dose in adults and children.

    Use of Domperidone and other drugs which prolong QTc intervals requires that caution be exercised in patients who have existing prolongation of cardiac conduction intervals, particularly QTc, patients with significant electrolyte disturbances or underlying cardiac diseases such as congestive heart failure.

    Chronic administration of domperidone is not recommended.

    New ADRs reported post-market: Ventricular arrhythmias and sudden cardiac death.

  • Dutasteride (Avodart®, GSK) Special warnings & precautions: Patients receiving Avodart® should have a new prostate-specific antigen (PSA) baseline established after 6 months of treatment with Avodart®. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on Avodart® may signal the presence of prostate cancer (particularly high grade cancer) or non-compliance to therapy with Avodart® and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5 alpha-reductase inhibitor. In the interpretation of a PSA value for a patient taking Avodart®, previous PSA values should be sought for comparison.

    In a 4-year study of over 8,000 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL (the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) study), 1,517 men were diagnosed with prostate cancer. There was a higher incidence of Gleason 8-10 prostate cancers in the Avodart® group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%). The clinical significance of the numerical imbalance is unknown. Men taking Avodart® should be regularly evaluated for prostate cancer risk including PSA testing.

    5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established.

    The relationship between Avodart® and high grade prostate cancer is not clear.

    New ADRs reported post-market: Alopecia (primarily body hair loss), hypertrichosis.

  • Ergometrine, oxytocin (Syntometrine®, Novartis) Warnings & precautions: Active management of the third stage of labour requires expert obstetric supervision.

    Syntometrine® has the potential to cause serious adverse drug reactions in breastfed newborns/infants. Postpartum women receiving Syntometrine® should avoid breastfeeding at least 12 hours after the administration. Milk secreted during this period should be expressed and discarded.

    Caution is required in patients with mild or moderate hypertension, cardiac disorder, or hepatic or renal impairment. Severe forms are contraindications. Patients with coronary artery disease may be more susceptible to myocardial ischaemia and infarction caused by ergometrine-induced vasospasm.

    Oxytocin should be considered as potentially arrhythmogenic. Caution is required when using Syntometrine® in patients with other risk factors for torsades de pointes such as drugs which prolong the QT interval or in patients with a history of long QT syndrome.

    Ergot alkaloids are substrates of CYP3A4. The concomitant use of Syntometrine® with strong CYP3A4 inhibitors such as macrolide antibiotics (e.g. troleandomycin, erythromycin, clarithromycin), HIV protease or reverse transcriptase inhibitors (e.g. ritonavir, indinavir, nelfinavir, delavirdine), or azole antifungals (e.g. ketoconazole, itraconazole, voriconazole) should be avoided, since this can result in an elevated exposure to methylergometrine and ergot toxicity (vasospasm and ischaemia of the extremities and other tissues). Caution should be exercised when Syntometrine® is used concurrently with other vasoconstrictors or other ergot alkaloids. Concurrent use of vasoconstrictors and Syntometrine® after delivery during anaesthesia may lead to severe postpartum hypertension. Methylergometrine may enhance the vasoconstrictor/vasopressor effects of other drugs such as triptans (5HT1B/1D receptor agonists), sympathomimetics (including those in local anaesthetics), beta-blockers or other ergot alkaloids.

    Caution is required when using Syntometrine® alone or in combination with prostaglandins and their analogues in the treatment of postpartum atonic uterine haemorrhage.

    Intravenous administration of Syntometrine® (0.5 to 1 ml by slow injection) is possible, but should be limited to use only in cases of severe haemorrhage due to uterine atony.

    Interactions: Syntometrine® may enhance the vasopressor effects of vasoconstrictors and sympathomimetics, even those contained in local anaesthetics.

    Prostaglandins and their analogues facilitate contraction of the myometrium hence Syntometrine® can potentiate the uterine action of prostaglandins and analogues and vice versa.

    Inhalation anaesthetics (e.g. halothane, cyclopropane, sevoflurane, desflurane, isoflurane) have a relaxing effect on uterus and produce a notable inhibition of uterine tone and thereby, may diminish the uterotonic effect of Syntometrine®.

    Oxytocin should be considered as potentially arrhythmogenic, particularly in patients with other risk factors for torsades de pointes such as drugs which prolong the QT interval or in patients with history of long QT syndrome.

    Strong CYP3A4 inhibitors such as protease inhibitors, macrolide antibiotics (e.g. troleandomycin, erythromycin, clarithromycin), HIV protease or reverse transcriptase inhibitors (e.g. ritonavir, indinavir, nelfinavir, delavirdine), azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), quinolones might raise the levels of ergot derivatives, which may lead to ergotism. Combined use with Syntometrine® should be avoided. Other weaker CYP3A4 inhibitors (e.g. cimetidine, grapefruit juice, quinupristin, dalfopristin) might interact similarly, although possibly to a lesser extent.

    Concurrent use of other ergot alkaloids (e.g. methysergide) and other ergot derivatives can increase the risk of severe and persistent spasm of major arteries in some patients.

    Additive vasoconstriction may occur when ergometrine is concomitantly given with triptans (e.g. sumatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan).

    Concomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.

    Ergometrine produces vasoconstriction and can be expected to reduce the effect of glyceryl trinitrate and other antianginal drugs.

    CYP3A4 inducers (e.g. nevirapine, rifampicin) may reduce the clinical effect of ergometrine.

    New ADRs reported post-market: Cerebrovascular accident, anaphylactoid reactions, myocardial infarction, coronary arteriospasm.

    Pregnancy & breastfeeding: Ergometrine has potent uterotonic activity. Therefore, Syntometrine® is contraindicated during pregnancy and during induction of labour; first stage labour and second stage labour prior to the delivery of the anterior shoulder.

    In breech presentation and other abnormal presentations, Syntometrine® should not be given before delivery of the child is completed, and in multiple birth not before the last child has been delivered.

    Ergometrine is secreted into milk and the inhibitory effect of ergometrine on prolactin can cause a reduction in milk secretion. Syntometrine® has the potential to cause serious adverse drug reactions in breastfed newborns/infants. Postpartum women receiving Syntometrine® should avoid breastfeeding at least 12 hours after the administration. Milk secreted during this period should be discarded. Breastfeeding should be discontinued in cases where repeated postpartum administration of Syntometrine® is necessary.

    Special populations: No studies have been performed in patients with renal or hepatic impairment. However considering the metabolic pathway of ergometrine and oxytocin, use is contraindicated in severe hepatic and renal impairment and caution is required in mild or moderate hepatic and renal impairment.

    No studies have been performed in paediatric patients. Syntometrine® is not indicated for use in children.

  • Ertapenem (Invanz®, MSD) New ADRs reported post-market: Muscular weakness, gait disturbance.

  • Everolimus (Certican®, Novartis) Special warnings & precautions: Caution is advised with the use of thymoglobulin (rabbit anti-thymocyte globulin) induction and the Certican®/ciclosporin/steroid regimen. In a clinical study in heart transplant recipients, an increased incidence of serious infections was observed within the first three months after transplantation in the subgroup of patients who had received induction with rabbit anti-thymocyte globulin combined with Certican®, steroid and ciclosporin at the blood concentration recommended for heart transplantation (higher than in kidney transplantation). This was associated with greater mortality among patients who were both hospitalized and required ventricular assistance device prior to transplantation suggesting that they may have been particularly vulnerable to increased immunosuppression.

  • Fluconazole (Diflucan®, Pfizer) Contraindications: Coadministration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide and quinidine are contraindicated in patients receiving fluconazole.

    Special warnings & precautions: Fluconazole should be administered with caution to patients with liver dysfunction.

    Fluconazole should be administered with caution to patients with renal dysfunction.

    Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9 and CYP3A4 should be monitored.

    Diflucan® capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

    Diflucan® powder for oral suspension contains sucrose and should not be used in patients with hereditary fructose, glucose/galactose malabsorption and sucrase-isomaltase deficiency.

    Interactions: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.

    Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.

    Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated.

    Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Coadministration of fluconazole and erythromycin is contraindicated.

    Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. There is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole.

    A study observed a reduction in clearance and distribution volume as well as prolongation of T½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

    Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.

    Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

    Dose adjustment of warfarin may be necessary during concomitant administration of fluconazole and warfarin.

    Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmaxwith 20-32% and increases t½by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

    Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

    Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

    During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmaxand AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

    Fluconazole significantly increases the concentration and AUC of cyclosporin. This combination may be used by reducing the dosage of cyclosporin depending on cyclosporin concentration.

    Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

    One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

    Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

    The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

    Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.

    Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

    The Cmaxand AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmaxand AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

    Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

    Fluconazole inhibits the hepatic metabolism of phenytoin. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

    There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

    Fluconazole increases the AUC of saquinavir with approximately 50%, Cmaxwith approximately 55% and decreases clearance of saquinavir with approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

    Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

    Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during coadministration.

    Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

    Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

    Based on a case report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.

    Fluconazole increases Cmaxand AUC of zidovudine by 84% and 74%, respectively, due to an approximate 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.

    Concurrent administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) which is a CYP2C9, CYP2C19 and CYP3A4 inhibitor, and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in C, and AUC, of voriconazole by an average of 57% (90% C1: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended.

    New ADRs include: Acute generalised exanthematous pustulosis, anaemia, decreased appetite, hepatic toxicity (including rare cases of fatalities).

    Pregnancy: Data from several hundred pregnant women treated with doses <200 mg/day of fluconazole, administered as a single or repeated dosage in the first trimester, show no undesired effects in the foetus.

    A few published case reports describe a distinctive and a rare pattern of birth defects among infants whose mother received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease.
  • Fluorouracil (DBL™ Fluorouracil, Hospira) Contraindications: Fluorouracil is contraindicated in patients- who are suffering from poor nutritional state,

    - who are suffering from bone marrow depression following radiotherapy or therapy with other antineoplastic agents (leucocyte count less than 5,000/mm3, platelet count less than 100, 000/ mm3).

    Precautions: Fluorouracil has a narrow margin of safety and is a highly toxic drug. Fluorouracil therapy should be discontinued promptly whenever one of the following signs of toxicity appears: leucopenia, thrombocytopenia, stomatitis, oesophagopharyngitis, intractable vomiting, diarrhoea, melena haemorrhage, oral ulceration, evidence of gastrointestinal ulceration or bleeding.

    Cytotoxic agents, including fluorouracil, may produce myelosuppression (including, but not limited to, leucopenia, granulocytopenia, pancytopenia and thrombocytopenia). Leucopenia and thrombocytopenia commonly follow treatment with fluorouracil.

    Clinical consequences of sever myelosuppression include infections. Viral, bacterial, fungal and/or parasitic infections, either localized or systemic, may be associated with the use of fluorouracil alone or in combination with other immunosuppressive agents. These infections may be mild, but can be severe and at times fatal.

    There is an increased risk of death associated with readministration of fluorouracil in patients with a documented cardiovascular reaction.

    Fluorouracil treatment may potentiate necrosis caused by radiation. Concomitant use of other chemotherapeutic agents may depress bone marrow function and increase the toxicity of fluorouracil.

    Fluorouracil should be used with caution in patients with renal and/ or hepatic dysfunction.

    Rarely, severe toxicity (e.g. stomatitis, diarrhoea, neutropenia, and neurotoxicity) associated with fluorouracil has been attributed to deficiency of dihydropyrimidine dehydrogenase (DPD) activity. Fatal outcome has been reported in some cases. Absence of this catabolic enzyme appears to result in prolonged clearance of fluorouracil. Special attention should be given to DPD status when evaluating patients experiencing fluorouracil-related toxicities.

    Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including fluorouracil, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving fluorouracil. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

    Interactions: All myelosuppressive drugs (e.g. cytotoxic agents used in combination chemotherapy) can increase haematotoxicity of fluorouracil.

    Folinic acid (Leucovorin) enhances the DNA-directed toxicity of fluorouracil. This combination should be used with caution as it is reported to increase the gastrointestinal toxicity of fluorouracil.

    Increased phenytoin plasma concentrations have been reported during concomitant use of phenytoin with capecitabine or its metabolite fluorouracil. Formal interaction studies between phenytoin and capecitabine have not been conducted, but the mechanism of interaction is presumed to be inhibition of CYP2C9 isoenzyme system by capecitabine. Serum levels of phenytoin sustained above the optimal range may produce encephalopathy, or confusional states (delirium, psychosis), or rarely irreversible cerebellar dysfunction. Therefore, patients taking phenytoin concomitantly with capecitabine or fluorouracil should be regularly monitored for increased phenytoin plasma levels.

    Fluorouracil could interfere with diagnostic tests of thyroid function by causing rises in total thyroxine and liothyronine due to increased globulin binding. Plasma albumin may be decreased because of drug-induced protein malabsorption.

    Adverse effects: The ratio between effective and toxic dose is small and therapy with fluorouracil is usually accompanied by some degree of adverse effects. Patients should be carefully observed and dosage adjustment may have to be made. Deaths have been reported.

    Partial loss of nails, dermatitis and hyperpigmentation of the nail beds and other body areas have been reported. Thrombophlebitis and photosensitivity reaction have also been reported. Continuous infusion fluorouracil may increase incidence and severity of palmar-plantar erythrodysaesthesia.

    Leucopenia, primarily granulocytopenia commonly occurs. The nadir for white blood cell count usually occurs from the 9th to the 14th day after initiation of therapy, but may occur as late as the 25th day. The count usually returns to normal by the 30th day. Thrombocytopenia may also occur, with the lowest platelet counts occurring from the 7th to the 17th day of therapy.

    Combination therapy with 5-fluorouracil and levamisole has been associated with multifocal inflammatory leukoencephalopathy (MILE). Symptoms may include memory loss, confusion, paraesthesia, lethargy, muscle weakness, speech disturbances, coma and seizures. The cerebrospinal fluid may show mild pleiocytosis, and computed tomography and magnetic resonance scans may show lesions in the white matter suggestive of demyelination. If this syndrome occurs, treatment should be discontinued immediately. The condition is at least partially reversible if 5-fluorouracil and levamisole are discontinued and corticosteroids given.

    Septic shock, sepsis, neutropenic sepsis, pneumonia, superinfection, urinary tract infection, catheter-related infection, cellulitis, pharyngitis and other infections have been reported.

    Local injection site reaction has also been reported.

    Pregnancy: Safety for use in pregnancy has not been established. Fluorouracil should only be used in women of child bearing potential if the expected benefits outweigh the risks of therapy, and adequate contraception is used. If the patient becomes pregnant whilst receiving the drug she should be advised of the potential hazards on the foetus. Men undergoing fluorouracil treatment should also ensure they use effective contraceptive measures.

    Special populations: Fluorouracil should be used with caution in elderly patients. An age of 70 years or older and the female gender are statistically significant risk factors for severe toxicity from fluorouracil based chemotherapy. These effects may be additive in older women. While advanced age does not contraindicate the use of this type of chemotherapy, close monitoring for multiple organ toxicities and vigorous supportive care of those with toxicity are necessary.

  • Fluticasone (Flixotide™ Evohaler™, GSK) Interactions: During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving intranasal or inhaled fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.

    New ADR: Contusions.

  • Follitropin alfa (Gonal-f™, Merck) Special warnings & precautions: Patients with porphyria or a family history of porphyria should be closely monitored during treatment with Gonal-f™. Deterioration or a first appearance of this condition may require cessation of treatment.

    A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment.

    Very rarely, severe ovarian hyperstimulation syndrome (OHSS) may be complicated by ovarian torsion or thromboembolic events such as pulmonary embolism, ischaemic stroke or myocardial infarction.

    Independent risk factors for developing OHSS include polycystic ovarian syndrome high absolute or rapidly rising serum oestradiol levels [e.g. > 900 pg/ml or > 3,300 pmol/l in anovulation; > 3,000 pg/ml or > 11,000 pmol/l in assisted reproductive technologies (ART)] and large number of developing ovarian follicles (e.g. > 3 follicles of ≥ 14 mm in diameter in anovulation; ≥ 20 follicles of ≥ 12 mm in diameter in ART) and large numbers of oocytes retrieved in ART cycles.

    Adherence to recommended Gonal-f™ dosage and regimen of administration can minimise the risk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to early identify risk factors.

    There is evidence to suggest that human chorionic gonadotropin (hCG) plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur such as serum oestradiol level > 5,500 pg/ml or >20,200 pmol/l and/or ≥ 40 follicles in total, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or to use barrier contraceptive methods for at least 4 days.

    Mild or moderate OHSS usually resolves spontaneously.

    In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events. It should be noted however, that pregnancy itself as well as OHSS, also carry an increased risk of thromboembolic events.

    Interactions: Gonal-f™ should not be administered as mixture with other medicinal products, in the same injection, except lutropin alfa for which studies have shown that co-administration does not significantly alter the activity, stability, pharmacokinetic nor pharmacodynamic properties of the active substances.

    New ADRs include: Complication of severe OHSS, exacerbation or aggravation of asthma; anaphylactic reactions and shock.

    Special populations: There is no relevant use of Gonal-f™ in the elderly population. Safety and effectiveness of Gonal-f™ in elderly patients have not been established.

    Safety, efficacy and pharmacokinetics of Gonal-f™ in patients with renal or hepatic impairment have not been established.

  • Ibuprofen (Brufen®, Abbott) Adverse reactions: A transient sensation of burning in the mouth or throat may occur with ibuprofen syrup or ibuprofen granules.

    Brufen Retard® tablets should be swallowed whole and not chewed, broken, crushed or sucked on to avoid oral discomfort and throat irritation.

  • Icodextrin (Extraneal®, Baxter Healthcare) Contraindications: - maltose or isomaltose intolerance

    - glycogen storage disease

    - pre-existing severe lactic acidosis

    - uncorrectable mechanical defects that prevent effective peritoneal dialysis (PD) or increase the risk of infection

    - documented loss of peritoneal function or extensive adhesions that compromise peritoneal function

    Precautions & warnings: Extraneal® is not for intravenous administration.

    Do not administer if the solution is discoloured, cloudy, contains particulate matter or shows evidence of leakage or if seals are not intact.

    The drained fluid should be inspected for the presence of fibrin or cloudiness, which may indicate the presence of peritonitis.

    Safety and effectiveness in paediatric patients have not been established.

    Medicines may be lost during PD and may require replacement.

    Peritoneal dialysis should be done with caution in patients with abdominal conditions, including disruption of the peritoneal membrane and diaphragm by surgery, from congenital anomalies or trauma until healing is complete, abdominal tumours, abdominal wall infection, hernias, faecal fistula, colostomy, or ileostomy, frequent episodes of diverticulitis, inflammatory or ischaemic bowel disease, large polycystic kidneys, or other conditions that compromise the integrity of the abdominal wall, abdominal surface, or intra-abdominal cavity; and other conditions including aortic graft placement and severe pulmonary disease.

    Patients should be carefully monitored to avoid over- and underhydration, which may have severe consequences including congestive heart failure, volume depletion and shock. An accurate fluid balance record should be kept and the patient's body weight monitored.

    Overinfusion of an Extraneal® volume into the peritoneal cavity may be characterized by abdominal distension, feeling of fullness and/or shortness of breath. Treatment of Extraneal® overinfusion is to drain the Extraneal® from the peritoneal cavity.

    Potassium is omitted from Extraneal® solutions due to the risk of hyperkalaemia.

    In situations in which there is a normal serum potassium level or hypokalaemia, the addition of potassium chloride (up to a concentration of 4 mEq/L) may be indicated to prevent severe hypokalaemia and should be made after careful evaluation of serum and total body potassium, only under the direction of a physician.

    Fluid, haematology, blood chemistry, and electrolyte concentrations should be monitored periodically, including, magnesium and bicarbonate. If serum magnesium levels are low, oral magnesium supplements or peritoneal dialysis solutions containing higher magnesium concentrations may be used.

    In diabetic patients, blood glucose levels should be regularly monitored, and the dosage of insulin or other treatment for hyperglycaemia should be adjusted following initiation of treatment with Extraneal®.

    Decreases in serum sodium and chloride have been observed in patients using Extraneal®.

    Blood glucose measurement must be done with a glucose-specific method to prevent maltose interference.

    Glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase (GDO) – based methods must not be used.

    Also, the use of some glucose monitors and test strips using glucose dehydrogenase flavin-adenine dinucleotide (GDH-FAD) methodology has resulted in falsely elevated glucose readings due to the presence of maltose. The manufacturer(s) of the monitor and test strips should be contacted to determine if icodextrin or maltose causes interference or falsely elevated glucose results.

    If GDH-PQQ, GDO, or GDH-FAD–based methods are used, using Extraneal® may cause a falsely high glucose reading, which could result in the administration of more insulin than needed. Administration of more insulin than needed has caused hypoglycaemia, which has resulted in loss of consciousness, coma, neurological damage, and death.

    Additionally, falsely elevated blood glucose measurements due to maltose interference may mask true hypoglycaemia and allow it to go untreated with similar consequences.

    Falsely elevated glucose levels may be measured up to two weeks following cessation of Extraneal® therapy when GDH-PQQ, GDO, or GDH-FAD-based blood glucose monitors and test strips are used.

    Because GDH-PQQ, GDO, and GDH-FAD-based blood glucose monitors may be used in hospital settings, it is important that the health care providers of all peritoneal dialysis patients using Extraneal® carefully review the product information of the blood glucose testing system, including that of test strips, to determine if the system is appropriate for use with Extraneal®.

    To avoid improper insulin administration, educate all patients on Extraneal® therapy to alert health care providers of this interaction whenever they are admitted to the hospital. Encapsulating peritoneal sclerosis (EPS) is considered to be a known, rare complication of peritoneal dialysis therapy. EPS has been reported in patients using peritoneal dialysis solutions including Extraneal®. Infrequently, fatal outcomes of EPS have been reported with Extraneal®. If peritonitis occurs, the choice and dosage of antibiotics should be based upon the results of identification and sensitivity studies of the isolated organism(s) when possible. Prior to identification of the involved organism(s), broad-spectrum antibiotics may be indicated. Rarely, serious hypersensitivity reactions to Extraneal® have been reported such as toxic epidermal necrolysis, angioedema, serum sickness, erythema multiforme and vasculitis. If a serious reaction is suspected, discontinue Extraneal® and institute appropriate treatment as clinically indicated.

    Patients with severe lactic acidosis should not be treated with lactate-based peritoneal dialysis solutions. It is recommended that patients with conditions known to increase the risk of lactic acidosis [e.g. acute renal failure, inborn errors of metabolism, treatment with drugs such as metformin and nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)] must be monitored for occurrence of lactic acidosis before the start of treatment and during treatment with lactate-based peritoneal dialysis solutions. When prescribing the solution to be used for an individual patient, consideration should be given to the potential interaction between the dialysis treatment and therapy directed at other existing illnesses. Serum potassium levels should be monitored carefully in patients treated with cardiac glycosides.

    Interactions: No interaction studies have been conducted with Extraneal®. The blood concentration of dialyzable drugs may be reduced by peritoneal dialysis.

    An apparent decrease in serum amylase activity has been observed in patients administered Extraneal®.

    New ADRs: Influenza, furuncle, eosinophilia, parathyroid disorder, tachycardia, pulmonary oedema, gastric ulcer, exfoliative dermatitis.

    New ADRs reported post-market: Thrombocytopenia, vasculitis, serum sickness, shock hypoglycaemia, hypoglycaemic coma, sclerosing encapsulating peritonitis, fungal peritonitis, toxic epidermal necrolysis.
  • Iloprost (Ventavis®, Bayer) Special warnings & precautions: There is insufficient data for the use of Ventavis® in pregnant women. Therefore, women of childbearing potential should use effective contraceptive measures during treatment with Ventavis®.

    It is not known whether iloprost/metabolites are excreted in human milk. Therefore women should not breastfeed during treatment with Ventavis®.

    Interactions: Iloprost may increase the antihypertensive effect of vasodilating and antihypertensive agents. Caution is recommended in case of coadministration of Ventavis® with vasodilating or antihypertensive agents as dose adjustment might be required.

    Because iloprost inhibits platelet function, careful monitoring of the patients taking anticoagulants or other inhibitors of platelet aggregation according to common medical practice is recommended.

    New ADRs: Bleeding events, thrombocytopenia.

    Bleeding events (mostly epistaxis and haemoptysis) were very common as expected in this patient population with a high proportion of patients taking anticoagulant comedication. The risk of bleeding may be increased in patients when inhibitors of platelet aggregation or anticoagulants are given concomitantly.

    Life-threatening and/or fatal cases of bleeding events have been reported.

    Pregnancy: Women with pulmonary hypertension (PH) must avoid pregnancy as it may lead to life-threatening exacerbation of the disease.

  • Ivabradine (Coralan®, Servier) New ADRs: Syncope, hypotension & malaise (all possibly related to bradycardia), rash, erythema.

  • Lanthanum (Fosrenol®, LF Asia) Precautions: The use of Fosrenol® in clinical studies beyond 2 years is currently limited. However, treatment of subjects with Fosrenol® for up to 6 years has not demonstrated a change in the benefit/risk profile.

    Lanthanum is not metabolised by liver enzymes but it is most likely excreted in the bile. Conditions resulting in a marked reduction of bile flow may be associated with incrementally slower elimination of lanthanum, which may result in higher plasma levels and increased tissue deposition of lanthanum. As the liver is the principal organ of elimination of absorbed lanthanum monitoring of liver function tests is recommended. The effect of hepatic impairment on Fosrenol® pharmacokinetics has not been formally assessed. Due to its mechanism of action and the lack of liver metabolism, doses in hepatic impairment should not be modified, but patients should be monitored carefully.

    Fosrenol® should be used in patients with acute peptic ulcer, ulcerative colitis, Crohn's disease or bowel obstruction following careful assessment of benefit/ risk. Fosrenol® is known to cause constipation and therefore caution should be exercised in patients predisposed to bowel obstruction (e.g. previous abdominal surgery, peritonitis).

    Interactions: The bioavailability of oral ciprofloxacin was decreased by approximately 50% when taken with Fosrenol® in a single dose study in healthy volunteers. It is recommended that oral floxacin formulations are taken at least 2 hours before or 4 hours after Fosrenol®.

    Phosphate binders (including Fosrenol®) have been shown to reduce the absorption of levothyroxine. Consequently, thyroid hormone replacement therapy should not be taken within 2 hours of dosing with Fosrenol® and closer monitoring of TSH levels is recommended in patients receiving both medicinal products.
  • Letrozole (Femara®, Novartis) New ADRs: Carpal tunnel syndrome, 'trigger finger'.

  • Metoclopramide (Metoclopramide®, DHA) Warnings: Tardive dyskinesia may develop in patients treated with metoclopramide. The elderly, especially elderly women, appear to be at increased risk. The risk appears to increase with treatment length and the total amount of drug taken. Tardive dyskinesia is more likely to be irreversible with long-term treatment (over 12 weeks). Less frequently, tardive dyskinesia can develop with short-term treatment at low doses; in these cases, the symptoms are more likely to disappear either partially or completely over time, once treatment has been stopped. Tardive dyskinesia may not be easy to recognize in its early stages. Metoclopramide treatment beyond 12 weeks should be avoided, unless the benefit is judged to outweigh the risk.
  • Metronidazole (Metronidazole Fresenius®, Fresenius Kabi) Special warnings & precautions: Metronidazole has no direct activity against aerobic or facultative anaerobic bacteria.

    Regular clinical and laboratory monitoring are advised if administration of Metronidazole Fresenius® for more than 10 days is considered to be necessary.

    There is a possibility that after Trichomonas vaginalis has been eliminated a gonococcal infection might persist.

    The elimination half-life of metronidazole remains unchanged in the presence of renal failure. Therefore, the dosage of metronidazole needs no reduction. However, such patients retain the metabolites of metronidazole. The clinical significance of this is not known at present.

    In patients undergoing haemodialysis metronidazole and metabolites are efficiently removed during an 8 hour period of dialysis. Therefore, Metronidazole Fresenius® should be readministered immediately after haemodialysis.

    No routine adjustment in the dosage of Metronidazole Fresenius® needs to be made in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD).

    Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. Significant cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms of the encephalopathy. Therefore, Metronidazole Fresenius® should be administered with caution to patients with hepatic impairment.

    In case of severe hepatic failure and impairment of the haematopoiesis, e.g. granulocytopenia, Metronidazole Fresenius® should be used only in case of a positive benefit/ risk assessment.

    During the treatment with metronidazole occasionally leucopenia, granulocytopenia, and in very rare cases agranulocytosis and thrombocytosis can occur. Therefore, regular controls of blood count are advised in case of a longer treatment with metronidazole.

    Metronidazole Fresenius® should be used with caution in patients with active or severe chronic disease of the peripheral nervous system and central nervous system. There are isolated reports about the occurrence of seizures and peripheral neuropathies, mainly numbness and paraesthesia of the limbs, during the treatment with metronidazole. In very rare cases, especially in long-term therapy with metronidazole in high dosages, structural cerebellar lesions with respective symptoms could be seen in MRI; cessation of metronidazole treatment usually results in relief of the symptoms and resolution of the structural lesions. In the evidence of neurological disorders, the benefit/ risk ratio has to be reassessed immediately with respect to the continuation of the metronidazole therapy.

    In case of severe hypersensitivity reactions, e.g. anaphylactic shock, the administration of Metronidazole Fresenius® has to be stopped immediately and the usual emergency measures have to be initiated by appropriate qualified personnel.

    Severe and persistent diarrhoea occurring during the treatment with Metronidazole Fresenius® or in the subsequent weeks can be caused by pseudomembranous enterocolitis (in most cases by Clostridium difficile) which can be life-threatening. In this case the treatment with Metronidazole Fresenius® has to be abandoned immediately and an adequate treatment has to be initiated. Medicinal products inhibiting peristalsis have to be avoided.

    The daily dosage of Metronidazole Fresenius® should be reduced to one third and may be administered once daily in patients with severe liver insufficiency.

    Caution is advised in elderly, particularly at high doses, although there is limited information available on modification of dosage.

    This medicinal product contains 13.5 mmol (310 mg) of sodium per 100 ml of solution. This should be taken into account in patients on a controlled sodium diet and in cases where fluid restriction is required.

    Interactions: Caution is advisable in case of administration of lithium containing medicinal products because an increase of serum lithium concentrations has been reported resulting in signs of lithium toxicity (tremor, convulsions). Lithium retention is accompanied by evidence of possible renal damage. Therefore, lithium treatment should be tapered or withdrawn before administering metronidazole. Plasma concentrations of lithium, creatinine and electrolytes should be monitored in patients under treatment with lithium while they receive metronidazole.

    Concomitant administration of barbiturates (hexobarbital or phenobarbital) containing medicinal products induces a reduction in the effectiveness of metronidazole by shortening the elimination half-life to approximately 3 hours.

    Metronidazole inhibits the metabolism of concomitantly administered phenytoin whereby the plasma concentration of phenytoin is increased. Simultaneously, phenytoin decreases the effectiveness of metronidazole.

    Metronidazole reduces the clearance of 5-fluorouracil and can therefore result in increased toxicity of 5-fluorouracil.

    Patients receiving ciclosporin are at risk of elevated ciclosporin serum levels. Serum ciclosporin and serum creatinine should be closely monitored when coadministration is necessary.

    Plasma levels of busulfan may be increased by metronidazole which may lead to severe busulfan toxicity.

    Metronidazole inhibits the metabolism of carbamazepine which leads to an increase of the plasma concentration of carbamazepine.

    Simultaneous administration of metronidazole results in an increase of the tacrolimus plasma level which has to be controlled frequently as well as the renal function, especially at the beginning and at the end of a metronidazole treatment in patients who are adjusted to a definite tacrolimus medication.

    Prolongation of QT intervals and torsade de pointes has been reported when metronidazole and amiodarone were administered concomitantly. Regular ECG controls are recommended. Outpatients are advised to consult their physicians in case of symptoms of torsade de pointes like drowsiness, palpitations, and sycope occur.

    In exceptional cases some antibiotics can decrease the effectiveness of oral contraceptives namely by inhibiting the bacterial hydrolysis of steroid conjugates and hence, a decrease of the reuptake of the unconjugated steroids in the gut. These exceptional interactions can occur in women with a high excretion of steroid conjugates via the bile.

    Substances like antibiotics which alter the intestinal flora may decrease the oral bioavailability of mycophenol acids. Close monitoring concerning a decrease of the immunosuppressive effects of mycophenol acids is advised when anti-infectives are administered concomitantly.

    New ADRs include: Aplastic anaemia, erythema multiforme, drug fever, Stevens-Johnson syndrome, toxic epidermal necrolysis, hallucinations, transient epileptiform seizures, aseptic meningitis, encephalopathy (e.g. confusion, fever, headache, paralysis, light sensitivity, visual disturbances, movement disturbances, stiff neck), subacute cerebellar syndrome (e.g. ataxia, dysarthria, gait impairment, nystagmus, and tremor), optic neuropathy, cholestatic hepatitis, phlebitis up to thrombophlebitis.

    Serious adverse reactions occur rarely with standard recommended regimens, rather at high dosages. Clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods longer than those recommended, are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.

    The most frequent undesirable effects are nausea, taste disorders, and the risk of the development of neuropathies in case of long-term treatment.

  • Omeprazole (Ramezol®, Shoei Universal) 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.
  • Pamidronate (Pamisol™, Hospira) Precautions: Disodium pamidronate should be administered under the supervision of a physician with the right equipment for the monitoring of clinical and biochemical parameters.

    Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported.

    Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit/ risk assessment.

    During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

    New ADRs reported post-market: Atypical subtrochanteric and diaphyseal femoral fractures, orbital inflammation.

  • Phenytoin (Dilantin®, Pfizer) Special warnings & precautions: Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for phenytoin.

  • Pioglitazone (Actos®, Invida) Contraindications: - active or history of bladder cancer

    - uninvestigated macroscopic haematuria

    Warnings & precautions: Studies-to-date suggest that use of pioglitazone for more than a year may be associated with an increased risk of bladder cancer.

    Preclinical and clinical trial data, and results from an observational study suggest an increased risk of bladder cancer in pioglitazone users. The observational data further suggest that the risk increases with duration of use. Do not use in patients with active or history of bladder cancer and in patients with uninvestigated macroscopic haematuria.

    Tumours were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which Actos® was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking Actos® compared to 5/3679 (0.14%) in patients not taking Actos®. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on Actos® and two (0.05%) cases on placebo.

    A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to Actos®, compared to subjects never exposed to Actos® (HR 1.2 [95% CI 0.9 – 1.5]). Compared to never exposure, a duration of Actos® therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 – 2.1]), which reached statistical significance after more than 24 months of Actos® use (HR 1.4 [95% CI 1.03 – 2.0]). Interim results from this study suggested that taking Actos® longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without Actos®] to approximately 10 in 10,000 [with Actos®]).

    There is insufficient data to determine whether pioglitazone is a tumour promoter for urinary bladder tumours. Consequently, Actos® should not be used in patients with active bladder cancer and in patients with a prior history of bladder cancer.

    Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment. Some of the risk factors include but is not limited to the following: current or past history of smoking, family history of bladder cancer, exposure to chemicals in the workplace or to certain cancer treatments such as cyclophosphamide and radiation therapy to abdomen or pelvis.

    Bladder cancer occurs more commonly in elderly patients and in men compared to women. Caution should be exercised when pioglitazone is to be prescribed for this group of patients.

    All patients prescribed pioglitazone should be counselled to seek medical attention if they experience blood in urine, urinary urgency, pain on urination, or back or abdominal pain, as these may be signs and symptoms of bladder cancer.

    Physicians are advised to review the treatment of patients on pioglitazone after three to six months (and regularly thereafter) to ensure that only patients with a favourable benefit/ risk profile continue treatment with pioglitazone. Existing patients on pioglitazone should be reviewed to ensure that the benefit/ risk profile remains favourable for continued use of pioglitazone.

  • Prasugrel (Effient®, Eli Lilly) Precautions: Thrombotic thrombocytopenic purpura has been reported with the use of Effient®.

    Hypersensitivity including angioedema has been reported in patients receiving Effient®, including in patients with a history of hypersensitivity reaction to other thienopyridines.

    New ADRs: Thrombotic thrombocytopenic purpura, thrombocytopenia, hypersensitivity including angioedema.

  • Sulfur hexafluoride (Sonovue®, LF Asia) New ADRs: Loss of consciousness, allergic reaction.

  • Sulpiride (Dogmatil®, sanofi-aventis) Special warnings & precautions: In randomized, placebo-controlled clinical trials in elderly patients with dementia and treated with atypical antipsychotics, a higher risk of stroke was observed versus placebo. The reason for this increased risk is unknown. Increased risk with other antipsychotics or in other patient populations cannot be ruled out. This drug should be used with caution in patients with risk factors for stroke.

    The risk of mortality increases in elderly patients suffering from dementia-related psychosis and treated with antipsychotic drugs.

    Analysis of 17 placebo-controlled studies (mean duration of 10 weeks), conducted in patients mainly taking atypical antipsychotic drugs, showed that the risk of mortality increased 1.6- to 1.7-fold in patients treated with these medicinal products versus placebo.

    After a mean treatment period of 10 weeks, the risk of mortality was 4.5% in the treated patient group versus 2.6% in the placebo group.

    Although the causes of death varied in the clinical trials with the atypical antipsychotic drugs, the majority of deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia).

    Epidemiological studies suggest that treatment with conventional antipsychotic drugs may increase mortality, as is the case for atypical antipsychotic drugs.

    The respective contribution of the antipsychotic drug and patient characteristics to the increase in mortality found in the epidemiological studies is unclear.

    Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotic drugs often present acquired risk factors for VTE, any potential risk factors for VTE must be identified before and during treatment with Dogmatil® and preventive measures should be taken.

    Administration of this medicinal product is not recommended with alcohol, levodopa, antiparkinsonian dopamine agonists, antiparasitic agents likely to induce torsades de pointes, methadone, other neuroleptics and medicinal products likely to induce torsades de pointes.

    The risk of onset of tardive dyskinesia must be taken into account, even at low doses, particularly in elderly subjects.

    Since efficacy and safety have not been fully studied in children, special precautions are required during the use of sulpiride. Given the cognitive effects, a yearly clinical examination evaluating learning ability is recommended. The dosage is to be regularly adjusted according to the child's clinical condition.

    Administration of tablets or capsules is contraindicated in children aged under 6 years due to the risk of choking.

    In patients with diabetes or with risk factors for diabetes who are starting treatment with sulpiride, appropriate blood glucose monitoring should be carried out.

    Cases of seizure have been reported in epileptic patients treated with sulpiride.

    Interactions: Sedatives have additive depressant effects on the central nervous system and contribute to a decrease in alertness. These drugs include morphine derivatives (analgesics, antitussives, and replacement therapies), neuroleptics, barbiturates, benzodiazepines, non-benzodiazepine anxiolytics (such as meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1-antihistamines, centrally-acting antihypertensives, baclofen, and thalidomide.

    Torsades de pointes can be caused by a number of medicinal products, anti-arrhythmics or not. Hypokalaemia is a promoting factor, as is bradycardia or pre-existing congenital or acquired QT interval prolongation. The medicines involved are in particular class Ia (quinidine, hydroquinidine, disopyramide) and III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics and certain neuroleptics (e.g. amisulpride, chlorpromazine, cyamemazine, droperidol, haloperidol).For erythromycin, spiramycin and vincamine, only intravenously administered dosage forms are affected by this interaction.

    Coadministration of two torsadogenic drugs is generally contraindicated.

    However, methadone, as well as certain sub-classes, are exceptions: - antiparasitics (halofantrine, lumefantrine, pentamidine) are merely not recommended in combination with other torsadogenic drugs. If possible, treatment with the azole antifungal agent should be discontinued. If coadministration cannot be avoided, QT interval should be checked before treatment and the ECG monitored;

    - neuroleptics likely to induce torsades de pointes are also not recommended, but not contraindicated, in combination with other torsadogenic drugs.

    Non-antiparkinsonian dopamine agonists (cabergoline, quinagolide) are contraindicated combinations with sulpiride.

    Caution is required when the following combinations are used: - Antihypertensives. Increased risk of hypotension, particularly postural.

    - beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Increased risk of ventricular arrhythmias, particularly torsades de pointes. Clinical and ECG monitoring required.

    - Beta blockers (except esmolol and sotalol and beta blockers used in heart failure). Vasodilator effect and risk of hypotension, particularly postural (additive effect).

    - Bradycardia-inducing drugs (in particular class Ia antiarrhythmics, beta blockers, certain class III antiarrhythmics, certain calcium channel blockers, digitalis glycosides, pilocarpine, anticholinesterases). Increased risk of ventricular arrhythmias, particularly torsades de pointes. Clinical and ECG monitoring required.

    - Nitrates, nitrites and related drugs. Increased risk of hypotension, particularly postural.

    - Potassium-depleting drugs (potassium-depleting diuretics, alone or in combination, stimulant laxatives, glucocorticoids, tetracosactide and amphotericin B IV). Increased risk of ventricular arrhythmias, particularly torsades de pointes. Any existing hypokalaemia should be corrected before administration, and clinical, electrolyte and ECG monitoring performed.

    - Sucralfate. Decreased gastrointestinal absorption of sulpiride. Allow for an interval between administration of sucralfate and sulpiride (more than 2 hours, if possible).

    - Topical agents for gastrointestinal use, antacids and charcoal. Decreased gastrointestinal absorption of sulpiride. Allow for an interval between administration of these agents and sulpiride (more than 2 hours, if possible).

    New ADRs: Seizures, potentially fatal neuroleptic malignant syndrome, torsades de pointes, ventricular tachycardia, ventricular fibrillation, cardiac arrest, sudden death, increase in hepatic enzymes, rash maculo-papular.

    Cases of VTE including pulmonary embolism & deep vein thrombosis, have been reported with antipsychotic drugs.

    Pregnancy: Good mental health should preferably be maintained throughout pregnancy to avoid decompensation. If drug therapy is necessary in order to ensure this mental well-being, it must be instituted or continued at an effective dose throughout pregnancy.

    Analysis of exposed pregnancies has not revealed any particular teratogenic effect with sulpiride.

    Injectable neuroleptics used in emergency situations can cause hypotension in the mother.

    Although no cases have been described in neonates, sulpiride could theoretically cause the following signs if continued to the end of pregnancy, particularly at high doses: - signs related to its atropine-like properties, exacerbated if combined with antiparkinsonian agents i.e. tachycardia, hyperexcitability, abdominal distension, delayed meconium excretion,

    - extrapyramidal signs i.e. hypertonia, tremor,

    - sedation.

    Consequently, as a precautionary measure, use of sulpiride should preferably be avoided during pregnancy. However, in the event of treatment with this medicinal product, it is advisable to limit the prescribed duration and dose during pregnancy insofar as possible. The above effects should be taken into account when monitoring the neonate.
  • Valsartan, Hydrochlorothiazide (Co-Diovan®, Novartis) Special warnings & precautions: Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate pre-existing hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt-losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia is accompanied by clinical signs (e.g. muscular weakness, paresis, or ECG alterations), Co-Diovan® should be discontinued. Correction of hypokalaemia and any coexisting hypomagnesaemia is recommended prior to the initiation of thiazides. Potassium and magnesium serum concentrations should be checked periodically. All patients receiving thiazide diuretics should be monitored for imbalances in electrolytes, particularly potassium. Thiazide diuretics can precipitate new onset hyponatraemia and hypochloraemic alkalosis or exacerbate pre-existing hyponatraemia. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. Regular monitoring of serum sodium concentrations is recommended.

    Co-Diovan® should be used only after correction of any pre-existing sodium and/ or volume depletion otherwise the treatment should start under close medical supervision.

    Due to the hydrochlorothiazide component, use of Co-Diovan® is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min). Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease.

    Co-Diovan® should be used with particular caution in patients with biliary obstructive disorders and is contraindicated in patients with severe hepatic impairment.

    Like other diuretics, hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricaemia and precipitate gout in susceptible patients.

    Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium in the absence of known disorders of calcium metabolism. Since hydrochlorothiazide can increase serum calcium concentrations, it is contraindicated in patients with hypercalcaemia. Marked hypercalcaemia unresponsive to thiazide withdrawal or ≥12 mg/dL may be evidence of an underlying thiazide independent hypercalcaemic process.

    Pathological changes in the parathyroid gland of patients with hypercalcaemia and hypophosphataemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcaemia occurs, further diagnostic clarification is necessary.

    Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

    Hydrochlorothiazide, a sulphonamide, has been associated with 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 week of a 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 treatment 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: When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, in patients who are elderly, volume-depleted (including those on diuretic therapy), or have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly.

    Thiazides potentiate the antihypertensive action of other antihypertensive drugs [e.g. guanethidine, methyldopa, beta blockers, vasodilators, calcium channel blockers, ACE inhibitors, Angiotensin Receptor Blockers (ARBs) and Direct Renin Inhibitors (DRIs)].

    Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives.

    The hypokalaemic effect of diuretics may be increased by concomitant administration of antiarrhythmics.

    The hyponatraemic effect of diuretics may be intensified by concomitant administration of drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these drugs.

    Thiazides may alter glucose tolerance. It may be necessary to adjust the dosage of insulin and of oral antidiabetic agents.

    Prokinetic drugs such as cisapride may decrease the bioavailability of thiazide-type diuretics.

    Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 h before or 4-6 h after the administration of resins would potentially minimize the interaction.

    Concomitant use of thiazide type diuretics may lead to hypercalcaemia by increasing tubular calcium reabsorption.

    Concomitant administration of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension.

    Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.

    ADRs reported in patients treated with thiazide diuretics alone, including hydrochlorothiazide: Hypercalcaemia, hyperglycaemia, glycosuria, worsening of diabetic metabolic state, hypokalaemia, hyponatraemia, hypomagnesaemia, hyperuricaemia, increased blood lipids, hypochloraemic alkalosis.

    ADRs reported post-market in patients treated with thiazide diuretics alone, including hydrochlorothiazide: Acute renal failure, renal disorder, aplastic anaemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma.