December 2011
- Adefovir (Hepsera®, GSK) ADR reported post-market: Osteomalacia (manifesting as bone pain and infrequently contributing to fractures).
- Amino acids, calcium chloride dihydrate, magnesium chloride hexahydrate, sodium chloride, sodium lactate (Nutrineal®, Baxter Healthcare) Contraindications:
− serum urea level above 38 mmol/L
- uraemic symptoms
- metabolic acidosis
- inborn errors of amino acid metabolism
- liver insufficiency
- severe hypokalaemia
Special warnings & precautions: 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 Nutrineal®.
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.
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.
Metabolic acidosis should be corrected before and during Nutrineal® treatment.
Protein, amino acids, water-soluble vitamins, and other medicines may be lost during peritoneal dialysis and may require replacement.
In patients using cardiac glycosides, plasma level of potassium, calcium, and magnesium must be carefully monitored.
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 or colostomy, large polycystic kidneys, or other conditions that compromise the integrity of the abdominal wall, abdominal surface, or intra-abdominal cavity
- other conditions including aortic graft placement and severe pulmonary disease.
Overinfusion of a peritoneal dialysis solution into the peritoneal cavity may be characterized by abdominal distension/abdominal pain and/or shortness of breath.
Treatment of peritoneal dialysis solution overinfusion is to drain the solution from the peritoneal cavity.
Patients should be carefully monitored to avoid over-and underhydration. An accurate fluid balance record must be kept and the body weight of the patient must carefully be monitored.
Potassium is omitted from Nutrineal® 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.
Serum electrolyte concentrations (particularly bicarbonate, potassium, magnesium, calcium and phosphate), blood chemistry (including parathyroid hormone) and haematological parameters should be evaluated periodically.
In patients with diabetes, blood glucose levels should be monitored and the dosage of insulin or other treatment for hyperglycaemia should be adjusted.
A portion of the amino acids in Nutrineal® is converted to metabolic nitrogenous waste, such as urea. If dialysis is insufficient, the additional metabolic waste generated by the use of Nutrineal® may lead to the appearance of uraemic symptoms such as anorexia or vomiting. Symptoms can be managed by discontinuation of Nutrineal® or an increased dialysis dose with a non amino acid based solution.
Interactions: No interaction studies have been conducted with Nutrineal®. Blood concentration of other dialyzable medicinal products may be reduced during dialysis.
New ADRs include: Catheter site infection, anaemia, acidosis, hypervolaemia, hypokalaemia, depression, increased blood urea.
New ADRs reported post-market include: Bacterial peritonitis, anorexia, peritoneal cloudy effluent, catheter related complication, pyrexia, abnormal peritoneal fluid analysis.
Pregnancy & lactation: There are no adequate data from the use of Nutrineal® in pregnant or lactating women. Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing Nutrineal®.
- Anidulafungin (Eraxis®, Pfizer) New ADRs: Hypotension, bronchospasm, dyspnoea.
- Aprepitant (Emend®, MSD) New ADRs include: Cardiovascular disorder, abdominal distension, decreased appetite, muscular weakness, gait disturbance, glusose urine present, decreased neutrophil count.
New ADRs reported post-market: Stevens-Jonhnson syndrome/toxic epidermal necrolysis. - Azelaic acid (Skinoren® cream, Invida) Special warnings & precautions: Care must be taken when using Skinoren® cream to avoid contact with the eyes, mouth and other mucous membranes, and patients should be instructed accordingly. In the event of accidental contact, the eyes, mouth and/or affected mucous membranes should be washed with large amount of water. If eye irritation persists, patients should consult a physician. The hands should be washed after each application of the Skinoren® cream.
Benzoic acid is mildly irritant to the skin, eyes and mucous membranes. Propylene glycol may cause skin irritation.
Skinoren® should not be used continuously for more than 12 months at any time.
New ADRs include: Application site exfoliation, application site pain, application site discolouration, application site paraesthesia, application site dermatitis, application site vesicles, application site eczema, application site ulcer, cheilitis, seborrhoea, acne, drug hypersensitivity.
In clinical studies, most frequently observed side effects included application site burning, application site pruritus, and application site erythema.
Rash has been reported rarely in post-marketing surveillance.
Worsening of asthma in patients treated with azelaic acid has been reported rarely during post-marketing surveillance.
Pregnancy & lactation: There are no adequate and well-controlled studies of topically administered azelaic acid in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy embryonal/foetal development, parturition or postnatal development.
It is advisable to avoid Skinoren® cream during pregnancy unless the benefit outweighs the risk.
It is not known if azelaic acid is secreted in human milk in vivo. However an in vitro equilibrium dialysis experiment demonstrated that passage of drug into maternal milk may occur. But the distribution of azelaic acid into maternal milk is not expected to cause a significant change from baseline azelaic acid levels in the milk since azelaic acid is not concentrated in milk and less than 4% of topically applied azelaic acid is systemically absorbed not increasing endogenous azelaic acid exposure above physiological levels. However, Skinoren® cream should not be used by lactating woman unless the benefit outweighs the risk. - Betahistine (Betaserc®, Abbott) Contraindication: Phaeochromocytoma.
Warnings & precautions: Patients with bronchial asthma and/or history of peptic (stomach) ulcer need to be carefully monitored during the therapy.
Interactions: As betahistine is similar in structure to histamine, interaction of betahistine with antihistamines may affect the efficacy of one of these drugs.
New ADR: Headache. - Budesonide (Pulmicort®, AstraZeneca) New ADR: Anaphylactic reaction.
- Clomipramine (Anafranil®, Novartis) Warnings & precautions: In patients with hepatic and renal disease, periodic monitoring of the hepatic enzyme levels and renal function is recommended.
Abrupt discontinuation of Anafranil® therapy should be avoided because of possible withdrawal symptoms. Therefore, dosage should be stopped gradually after regular use for long duration and the patient should be monitored carefully when Anafranil® therapy is discontinued.
Interactions: MAO inhibitors, which are also potent CYP2D6 inhibitors in vivo, such as moclobemide, are contraindicated for co-administration with clomipramine.
Concomitant administration of valproate with clomipramine may cause inhibition of CYP2C and/or UGT (UDP-glucuronosyltransferase) enzymes resulting in increased serum levels of clomipramine and desmethylclomipramine.
Concomitant administration of Anafranil® with grapefruit, grapefruit juice, or cranberry juice may increase the plasma concentrations of clomipramine.
Concomitant administration of ion exchange resins such as cholestyramine or colestipol may reduce the plasma levels of clomipramine. Staggering the dosage of clomipramine and resins, such that the drug is administered at least 2 h before or 4-6 h after the administration of resins, is recommended.
Concomitant administration of Anafranil® with St. John's wort during the treatment may decrease the plasma concentrations of clomipramine.
New ADRs reported post-market: Serotonin syndrome, extrapyramidal symptoms (including akathisia and tardive dyskinesia), rhabdomyolysis (as a complication of neuroleptic malignant syndrome), increased blood prolactin.
Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric, or cardiovascular effects. Their ability to metabolise and eliminate drugs may be reduced, leading to a risk of elevated plasma concentrations at therapeutic doses.
Special populations: Elderly patients generally show a stronger response to Anafranil® than patients of intermediate age groups, Anafranil® should be used with caution in elderly patients and doses should be increased cautiously.
Adolescents generally show a stronger response to Anafranil® than patients of intermediate age groups, Anafranil® should be used with caution in adolescents and doses should be increased cautiously.
Anafranil® should be given with caution in patients with renal and hepatic impairment. - Desferrioxamine (Desferal®, Novartis) Warnings & precautions: Monitoring patients for changes in renal function (e.g. increased serum creatinine) should be considered.
Desferal® should not be given in doses higher than recommended. The drug should not be given at concentrations higher than 95 mg/ml when given subcutaneously as this increases the risk of local reactions by the subcutaneous route.
Post-marketing reports suggest a possible trend for an increased risk of eye disorders in the geriatric population, specifically the occurrence of colour blindness, maculopathy, and scotoma. However, it is unclear if these eye disorders were dose-related. Although the number of reports was very small, certain elderly patients may be predisposed to eye disorders when taking Desferal®. Post-marketing reports also suggest that there may be an increased risk of deafness and hearing loss in the geriatric population. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
New ADRs: Tachycardia and shock- if precautions for administration are not adhered to.
Excretion of the iron complex may cause reddish-brown discolouration of the urine.
Desferal® chelation therapy aluminum overload may result in hypocalcaemia and aggravation of hyperparathyroidism.
Pregnancy & lactation: There is a limited amount of data on the use of desferrioxamine in pregnant patients. Studies in animals (rabbits) have shown reproductive toxicity/teratogenicity. The risk to the foetus/mother is unknown.
Desferrioxamine should be used during pregnancy only if the expected benefit outweighs the potential risk to the foetus especially in the first 3 months.
Because many drugs are excreted in human milk, and because of the potential for serious adverse drug reactions in breastfed newborns/infants, a decision should be made whether to abstain from breastfeeding or to abstain from using the medicinal product, taking into account the importance of the medicinal product to the mother. - Eltrombopag olamine (Revolade®, GSK) Special warnings & precautions: Use a lower starting dose of Revolade® and monitor closely when administering Revolade® to patients with liver cirrhosis (hepatic impairment).
The risk of thromboembolic events (TEEs) has been found to be increased in patients with chronic liver disease (CLD) treated with 75 mg Revolade® once daily for two weeks in preparation for invasive procedures. Six of 143 (4%) adult patients with CLD receiving Revolade® experienced TEEs (all of the portal venous system) and two of 145 (1 %) subjects in the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five of the 6 patients treated with Revolade® experienced the thrombotic complication at a platelet count > 200,000/μl and within 30 days of the last dose of Revolade®.
Revolade® should not be used in patients with hepatic impairment (Child-Pugh score ≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis. When treatment is considered appropriate exercise caution when administering Revolade® to ITP (immune thrombocytopenic purpura) patients with liver cirrhosis (hepatic impairment). - Estradiol, norgestrel (Progyluton®, Bayer) Contraindication: A high risk of venous or arterial thrombosis.
Special warnings & precautions: Before initiating therapy, all conditions/risk factors should be considered when determining the individual benefit/risk of treatment for the patient.
During hormone replacement therapy (HRT) use, therapy should be discontinued immediately in case a contraindication is discovered, as well as in the following situations:
i) Migrainous or frequent and unusually severe headaches that occur for the first time or other symptoms that are possible prodroma of cerebrovascular occlusion.
ii) Recurrence of cholestatic jaundice or cholestatic pruritus which occurred first during pregnancy or previous use of sex steroids.
iii) Symptoms of thrombotic event or suspicion thereof.
In the event of new onset or deterioration of conditions or risk factors, the individual benefit/risk analysis should be re-done, taking into consideration the possible necessity of discontinuing therapy.
The potential for an increase synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. HRT should not be prescribed in case of a negative risk-benefit assessment.
HRT increases the density of mammographic images which may adversely affect the radiological detection of breast cancer in some cases.
Close medical supervision (including periodic measurement of prolactin levels) is necessary during HRT treatment if the patient has a high risk of developing prolactinoma.
A complete medical history should be taken and a physical examination should be conducted prior to the initiation or reinstitution of HRT, guided by the contraindications and warnings and should be repeated periodically. The frequency and nature of these examinations should be based on established practice guidelines and be adapted to the individual woman, but should generally include pelvic organs, including routine cervical cytology, abdomen, breasts and blood pressure.
Special populations: Progyluton® is not indicated for use in children and adolescents.
Progyluton® is contraindicated in women with severe hepatic diseases.
Oestrogen may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
- Galantamine (Reminyl®, J & J) New ADR reported post-market: Hypersensitivity.
- Ibuprofen (Brufen®, Abbott) Contraindications:
- Ibuprofen is contraindicated in patients with severe heart failure.
- Ibuprofen is contraindicated in patients with severe liver failure.
- Ibuprofen is contraindicated in patients with severe renal failure (glomerular filtration below 30 ml/min).
- Ibuprofen should not be given to patients with conditions involving an increased tendency to bleeding.
- Ibuprofen is also contraindicated in patients with a history of gastrointestinal bleeding or perforation, related to previous NSAID therapy.
- Ibuprofen should not be used in patients with active, or a history of, ulcerative colitis, Crohn's disease, recurrent peptic ulceration or gastrointestinal haemorrhage (defined as two or more distinct episodes of proven ulceration or bleeding).
- Ibuprofen is contraindicated during the third trimester of pregnancy.
Warnings & precautions: Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.
As with other NSAIDs, ibuprofen may mask the signs of infection.
Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal.
Ibuprofen should be given with care to patients with a history of peptic ulceration and other gastrointestinal disease since their conditions may be exacerbated.
Gastrointestinal bleeding, ulceration or perforation has been reported with all NSAIDs at any time during treatment. These adverse events can be fatal and may occur with or without warning symptoms or a previous history of serious gastrointestinal events. The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing ibuprofen doses in patients with a history of ulcers, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available.
Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, as well as patients requiring concomitant low dose aspirin, or for other drugs likely to increase gastrointestinal risk.
The concomitant administration of ibuprofen and other NSAIDs, including cyclooxygenase-2 (COX-2) selective inhibitors, should be avoided due to the increased risk of ulceration or bleeding.
Patients with a history of gastrointestinal disease, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) in the initial stages of treatment.
Caution should be exercised in patients receiving concomitant medication which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin re-uptake inhibitors or antiplatelet drugs such as aspirin.
If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.
Caution is required if ibuprofen is administered to patients suffering from, or with a previous history of, bronchial asthma since ibuprofen has been reported to cause bronchospasm in such patients.
Caution is required in patients with renal, hepatic or cardiac impairment since the use of NSAIDs may result in deterioration of renal function. The dose should be kept as low as possible and renal function should be monitored in these patients.
Ibuprofen should be given with care to patients with a history of heart failure or hypertension since oedema has been reported in association with ibuprofen administration.
Epidemiological data suggest that use of ibuprofen, particularly at a high dose (2,400 mg daily) and in long-term treatment, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke. Epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤1,200 mg daily) is associated with an increased risk of arterial thrombotic events, particularly myocardial infarction.
Patients with uncontrolled hypertension, congestive heart failure, established iscahemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking).
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy. In the majority of cases, the onset of the reaction occurs within the first month of treatment. Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.
Caution should be used when initiating treatment with ibuprofen in patients with considerable dehydration.
As with other NSAIDs, long-term administration of ibuprofen has resulted in renal papillary necrosis and other renal pathologic changes. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Ibuprofen, like other NSAIDs, can inhibit platelet aggregation and has been shown to prolong bleeding time in normal subjects.
Aseptic meningitis has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease.
Interactions: NSAIDs may reduce the effect of anti-hypertensives, such as ACE inhibitors, beta-blockers and diuretics.
Diuretics can also increase the risk of nephrotoxicity of NSAIDs.
NSAIDs may decrease elimination of lithium.
NSAIDs may inhibit the tubular secretion of methotrexate and reduce clearance of methotrexate.
NSAIDs may enhance the effects of anticoagulants, such as warfarin.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) increase the risk of gastrointestinal bleeding with NSAIDs.
NSAIDs may decrease the excretion of aminoglycosides.
As with other products containing NSAIDs, concomitant administration of ibuprofen and aspirin is not generally recommended because of the potential of increased adverse effects.
Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.
NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma cardiac glycoside levels.
The concomitant administration of ibuprofen and cholestyramine may reduce the absorption of ibuprofen in the gastrointestinal tract. However, the clinical significance is unknown.
Cyclosporine increases the risk of nephrotoxicity with NSAIDs.
Corticosteroids increase the risk of gastrointestinal ulceration or bleeding with NSAIDs.
Concomitant use with other NSAIDs, including COX-2 selective inhibitors, should be avoided due to the potential for additive effects.
Ginkgo biloba may potentiate the risk of bleeding with NSAIDs.
A decrease in the efficacy of the medicinal product can theoretically occur due to the antiprostaglandin properties of NSAIDs. Limited evidence suggests that coadministration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medicinal termination of pregnancy.
Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
NSAIDs may potentiate the effects of sulfonylureas.
There have been rare reports of hypoglycaemia in patients on sulfonylureas receiving ibuprofen.
There is a possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
There is an increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
Concomitant administration of ibuprofen with CYP2C9 inhibitors may increase the exposure to ibuprofen (CYP2C9 substrate). In a study with voriconazole and fluconazole (CYP2C9 inhibitors), an increased S(+)-ibuprofen exposure by approximately 80 to 100% has been shown. Reduction of the ibuprofen dose should be considered when potent CYP2C9 inhibitors are administered concomitantly, particularly when high-dose ibuprofen is administered with either voriconazole or fluconazole.
Adverse reactions: Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reaction and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, very rarely, bullous dermatoses (including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme).
The most commonly observed adverse events are gastrointestinal in nature. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, gastrointestinal haemorrhage and exacerbation of colitis and Crohn's disease have been reported following ibuprofen administration. Less frequently, gastritis, duodenal ulcer and gastric ulcer have been observed.
Gastrointestinal perforation has been rarely reported with ibuprofen use.
Pancreatitis has also been reported very rarely.
Oedema and fatigue have been reported in association with ibuprofen treatment.
Other adverse events reported less commonly and for which causality has not necessarily been established include: Aseptic meningitis, leukopenia, thrombocytopenia, aplastic anaemia, neutropenia, agranulocytosis, haemolytic anaemia, depression, optic neuritis, toxic optic neuropathy, tinnitus, hepatic failure, photosensitivity reaction, interstitial nephritis, nephrotic syndrome, renal failure.
Pregnancy & lactation: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. In animals, the administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation losses and embryo/foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.
During the first and second trimester of pregnancy, ibuprofen should not be given unless clearly necessary. If ibuprofen is used by a woman attempting to conceive, or during the first or second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to the following:
- Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)
- Renal dysfunction, which may progress to renal failure with oligohydramnios.
At the end of pregnancy, prostaglandin synthesis inhibitors may expose the mother and the neonate to the following:
- Possible prolongation of bleeding time
- Inhibition of uterine contractions, which may result in delayed or prolonged labour.
Consequently, ibuprofen is contraindicated during the third trimester of pregnancy.
Administration of ibuprofen is not recommended during labour and delivery.
The onset of labour may be delayed and the duration increased with a greater bleeding tendency in both mother and child.
In the limited studies so far available, ibuprofen appears in the breast milk in very low concentrations. Ibuprofen is not recommended for use in nursing mothers.
- Insulin glulisine (Apidra®, sanofi-aventis) Special warnings & precautions: The Apidra® cartridges should only be used with the following pens: OptiPen®, ClikSTAR®, Tactipen® and Autopen 24® and should not be used with any other reusable pen as the dosing accuracy has only been established with the listed pens.
- Latanoprost, Timolol maleate (Xalacom®, Pfizer) Special warnings & precautions: Latanoprost should be used with caution in patients with a history of herpetic keratitis, and should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.
New ADRs reported post-market with latanoprost: Photophobia; periorbital and lid changes resulting in deepening of the eyelid sulcus; herpetic keratitis. - Lenalidomide (Revlimid®, Celgene) Special warnings & precautions: An increase of second primary malignancies (SPM) has been observed in clinical trials in previously treated myeloma patients receiving lenalidomide/dexamethasone (3.98 per 100 patient-years) compared to controls (1.38 per 100 patient-years). Non-invasive SPM comprise basal cell or squamous cell skin cancers. Most of the invasive SPMs were solid tumour malignancies.
The risk of occurrence of SPM must be taken into account before initiating treatment with Revlimid®. Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of second primary malignancies and institute treatment as indicated.
New ADR: Squamous skin cancer. - Loteprednol etabonate (Alrex®, Bausch & Lomb) Pregnancy: There are no adequate and well-controlled studies in pregnant women. Alrex® ophthalmic suspension should not be used in pregnant women, unless the potential benefit clearly outweighs the potential risk to the foetus.
- Norfloxacin (Gyrablock®, Medochemie);
- Ofloxacin (Akilen®, Euro Asia Medico; Oflotas®, Apotheca)
Precautions: Caution should be taken when using fluoroquinolones, including norfloxacin and ofloxacin, in patients with known risk factors for prolongation of the QT interval such as congenital long QT syndrome, concomitant use of drugs that are known to prolong the QT interval (e.g. class IA and III antiarrythmics, tricyclic antidepressants, macrolides, antipsychotics), uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia), elderly, cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
Fluoroquinolones, including norfloxacin and ofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid norfloxacin and ofloxacin in patients with a known history of myasthenia gravis.
Interactions: Norfloxacin and ofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. class IA and III antiarrythmics, tricyclic antidepressants, macrolides, antipsychotics).
New ADRs: Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), prolonged ECG QT, exacerbation of myasthenia gravis. - Omeprazole (Omeprazole 40®, Novartis; Probitor®, FP Marketing; Zenpro®, Apex Pharma) Special warnings & precautions: Hypomagnesaemia, symptomatic and asymptomatic, has been reported rarely in patients treated with proton pump inhibitors (PPIs) for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesaemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically.
New ADRs reported for Zenpro®: Pruritus, dizziness, fatigue, constipation, nausea, vomiting, flatulence, abdominal pain, urticaria, dry mouth. - Ondansetron (Zofran®, GSK) Contraindications/Interactions: Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.
New ADR: QTc prolongation (including torsade de pointes). - Ondansetron (Odnatron® & Setronax® injection, DHA) Warnings & precautions: Rarely, transient ECG changes including QT interval prolongation have been reported in patients receiving ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Ondansetron should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with electrolyte abnormalities, with congenital long QT syndrome, or patients taking other medicinal products that lead to QT prolongation.
- Phenytoin (Dilantin® steri-vial injection, Pfizer) Special warnings & precautions: Oedema, discolouration and pain distal to the site of injection (described as “purple glove syndrome”) have been reported following peripheral intravenous phenytoin injection. Soft tissue irritation may vary from slight tenderness to extensive necrosis, and sloughing of skin. The syndrome may not develop for several days after injection. Although resolution of symptoms may be spontaneous, skin necrosis and limb ischaemia have occurred and required such interventions as fasciotomies, skin grafting, and, in rare cases, amputation.
Because of the risk of local toxicity, intravenous phenytoin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral phenytoin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution.
Intramuscular phenytoin administration may cause pain, necrosis, and abscess formation at the injection site.
New ADR: Oedema, discolouration and pain distal to the site of injection (described as “purple glove syndrome”).
- Pramipexole (Sifrol®, Boehringer Ingelheim) New ADR: Cardiac failure.
In clinical studies and post-marketing experience cardiac failure has been reported in patients with pramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole. A causal relationship between pramipexole and cardiac failure has not been demonstrated.
- Saquinavir (Invirase®, Roche) Contraindications: Ritonavir-boosted Invirase® is contraindicated with some drugs that have both pharmacokinetic interactions and prolong the QT and/or PR interval and in patients with congenital or documented acquired QT prolongation, and electrolyte disturbances particularly uncorrected hypokalaemia.
The use of oral midazolam is contraindicated with Invirase®/ritonavir.
Special warnings & precautions: Dose-dependent prolongations of QT and PR intervals have been observed in healthy volunteers receiving ritonavir-boosted Invirase®.
It is not recommended to administer boosted Invirase® to patients concurrently with other medicinal products that prolong the QT interval. Caution is advised if concomitant use is considered necessary and an ECG performed if signs of cardiac arrhythmias occur. Ritonavir-boosted Invirase® should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, and ischaemic heart disease or cardiomyopathies as they may be at increased risk for developing cardiac conduction abnormalities.
Ritonavir-boosted Invirase® should be discontinued if significant arrhythmias, QT or PR prolongation occur. Generally, women and elderly patients may be more susceptible to drug-associated effects on the QT interval. The magnitude of QT and PR prolongation may increase with increasing concentrations of the drug. Therefore, the recommended dose of ritonavir-boosted Invirase® should not be exceeded. Ritonavir-boosted Invirase® at a dose of 2000 mg once daily with ritonavir 100 mg once daily has not been studied with regard to the risk of QT prolongation and is not recommended.
An ECG should be performed prior to initiation of treatment. Patients with a QT interval > 450 msec should not use ritonavir-boosted Invirase®. For patients with a QT interval < 450 msec, an on-treatment ECG is suggested after approximately 3 to 4 days of therapy and for patients with a QT interval > 480 msec or prolongation over pretreatment by > 20 msec should discontinue ritonavir- boosted Invirase®.
Patients stable on ritonavir-boosted Invirase® and requiring concomitant medication with potential to increase the QT interval or patients on medication with potential to increase the QT interval and requiring concomitant ritonavir-boosted Invirase® where no alternative therapy is available and the benefits outweigh the risks: An ECG should be performed prior to initiation of the concomitant therapy, and patients with a QT interval > 450 msec should not initiate the concomitant therapy. If baseline QT interval < 450 msec, an on-treatment ECGs should be performed. For patients demonstrating a subsequent increase in QT interval to > 480 msec or increase by > 20 msec after commencing concomitant therapy, the physician should use best clinical judgment to discontinue either ritonavir-boosted Invirase® or the concomitant therapy or both.
Close monitoring of safety (including signs of cardiac arrhythmia) and of virologic response is recommended in patients with moderate hepatic impairment due to increased variability of the exposure in this population. Invirase®/ritonavir is contraindicated in patients with severe hepatic impairment.
Interactions: Dose adjustment of rifabutin (150 mg q4d) is recommended when used in combination with ritonavir-boosted Invirase®.
Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers receiving ritonavir-boosted Invirase®, additive effects on QT and PR interval prolongation may occur with the following drug classes: Antiarrhythmics class IA or class III, neuroleptics, tricyclic antidepressive agents, PDE5 inhibitors, certain antimicrobials, certain antihistaminics and others. This effect might lead to an increased risk of ventricular arrhythmias, notably torsade de pointes. Therefore, concurrent administration of these agents with ritonavir-boosted Invirase® should be avoided when alternative treatment options are available. Medical products showing both pharmacokinetic interactions with ritonavir-boosted Invirase® and additive effects on QT and PR interval prolongation are strictly contraindicated. The combination of ritonavir-boosted Invirase® with other drugs known to prolong the QT and PR interval is not recommended and should be used with caution if concomitant use is deemed necessary.
Use lopinavir/ritonavir with caution as additive effects on QT and/or PR interval prolongation may occur with ritonavir-boosted Invirase®.
The effect of multiple dose ritonavir-boosted Invirase® (1000/100 mg) bd on the steadystate pharmacokinetics of nelfinavir (1250 mg bd) was evaluated in 12 HIV-infected patients. The geometric mean ratios of nelfinavir AUC0-12h and Cmax in the presence and absence of ritonavir-boosted Invirase® was 0.94 (90% CI: 0.72 to 1.22) and 0.95 (90% CI: 0.77 to 1.16) respectively. The nelfinavir M8 metabolite AUC0-12h and Cmax were increased by 2.25-fold (90% CI: 1.47 to 3.44) and 1.74-fold (90% CI: 1.25 to 2.40) respectively, in the presence of ritonavir-boosted Invirase® but did not alter the safety profile of nelfinavir.
The effect of multiple dose nelfinavir (1250 mg bd) on the steady-state pharmacokinetics of ritonavir-boosted Invirase® (1000/100 mg) bd was evaluated in 12 HIV-infected patients. The geometric mean ratios of saquinavir AUC0-12h and Cmax in the presence and absence of nelfinavir were 1.13 (90% CI: 0.73 to 1.74) and 1.09 (90% CI: 0.73 to 1.61) respectively.
Ritonavir-boosted Invirase® combined with nelfinavir administered to 24 HIV-infected patients for a short treatment duration of 7 days was tolerated. However, concomitant administration of nelfinavir and saquinavir soft gel capsules resulted in a moderate increase in the incidence of diarrhoea.
Antiarrhythmics, i.e. bepridil, systemic lidocaine, quinidine, are contraindicated in combination with ritonavir-boosted Invirase® due to potentially life-threatening cardiac arrhythmia.
Concomitant use of trazodone and ritonavir-boosted Invirase® may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. Trazodone is contraindicated in combination with ritonavir-boosted Invirase® due to potentially life-threatening cardiac arrhythmia.
Use erythromycin with caution as additive effects on QT and/or PR interval prolongation may occur with ritonavir-boosted Invirase®.
Data from a drug-drug interaction study involving 200 mg/day ketoconazole and ritonavir-boosted Invirase® (1000/100 mg) bd in 20 healthy subjects indicated that Cmax and AUC0-12h of both saquinavir and ritonavir at steady-state are not altered. This indicates that no dose adjustment for either Invirase® or ritonavir is required when co-administered with ≤ 200 mg ketoconazole. The effect of ritonavir-boosted Invirase® (1000/100 mg) bd on the pharmacokinetics of ketoconazole (200 mg/day) was studied in 12 healthy subjects. The Cmax and AUC0-24h of ketoconazole at steady-state increased by 45% (90% CI: 32% to 59%) and 168% (90% CI: 146% to 193%) respectively, in the presence of ritonavir-boosted Invirase® (1000/100 mg) bd. These results should be taken into account when dosing ketoconazole with ritonavir-boosted Invirase®. Hence, high doses of ketoconazole (> 200 mg/day) are not recommended.
The effect of multiple dose rifabutin on the pharmacokinetics of Invirase/ritonavir (1000/100 mg bd) was assessed in 25 healthy volunteers. Rifabutin appeared to slightly reduce the AUC0-12hr and Cmax of saquinavir by 13% (90% CI: -31% to 9%) and 15% (90% CI: -32% to 7%), respectively, for healthy volunteers receiving rifabutin 150 mg once every three days (q3d) with Invirase®/ritonavir (1000/100 mg bd). No effect of rifabutin on ritonavir AUC0-12hr (90% CI: -10% to 9%) and Cmax (90% CI: -8% to 7%) were observed. No dose adjustment of Invirase®/ritonavir (1000/100 mg bd) is required if ritonavir-boosted Invirase® is administered in combination with rifabutin.
The effect of multiple dose Invirase/ritonavir (1000/100 mg bd) on the pharmacokinetics of rifabutin was evaluated in 2 groups of healthy volunteers. In the first group (n=14), rifabutin 150 mg q3d was co-administered with Invirase®/ritonavir (1000/100 mg bd); the AUC0-72hr and Cmax of the active moiety (rifabutin + 25-O-desacetyl rifabutin) increased by 134% (90% CI: 109% to 162%) and 130% (90% CI: 98% to 167%), respectively, in comparison to those when rifabutin 150 mg daily was administered alone. Whereas, the exposure of rifabutin increased by 53% (90% CI: 36% to 73%) for AUC0-72hr and by 86% (90% CI: 57% to 119%) for Cmax. In the second group (n=13), rifabutin 150 mg q4d was co-administered with Invirase®/ritonavir (1000/100 mg bd); the AUC0-96hr and Cmax of the active moiety increased by 60% (90% CI: 43% to 79%) and 111% (90% CI: 75% to 153%), respectively, in comparison to those when rifabutin 150 mg daily was administered alone. In this second group, the exposure of rifabutin was not affected for AUC0
-96hr (90% CI: -10% to 13%) and increased by 68% (90% CI: 38% to 105%) for Cmax.Hence, the recommended dose of rifabutin is 150 mg every 4 days (q4d) when used in combination with ritonavir-boosted Invirase® (1000/100 mg bd). Monitoring of neutropenia and liver enzyme levels is recommended for patients receiving ritonavir-boosted Invirase® (1000/100 mg bd) and 150mg rifabutin (q4d).
Based on extrapolation from existing data, twice weekly dosing of rifabutin (e.g. Monday, Thursday) is not recommended with ritonavir-boosted Invirase® (1000/100 mg bd) as this would lead to pharmacokinetic exposure of rifabutin active moiety approximating that achieved at 300 mg rifabutin daily which may lead to a higher incidence or severity of rifabutin associated adverse events.
Caution should be used with parenteral midazolam. No data is available on the concomitant use of ritonavir-boosted Invirase® with intravenous midazolam. Studies of other CYP3A modulators and intravenous midazolam suggest a possible 3 to 4-fold increase in midazolam plasma levels. If Invirase® is coadministered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment should be considered, especially if more than a single dose of midazolam is administered.
If omeprazole or another proton pump inhibitor is used concomitantly with Invirase®/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis and QT prolongation.
Use methadone with caution as additive effects on QT and/or PR interval prolongation may occur with ritonavir-boosted Invirase®.
Co-administration of pimozide and ritonavir-boosted Invirase® may lead to an increase in pimozide exposure (AUC) associated with additive effects on QT and/or PR interval prolongation. Hence, pimozide is contraindicated in patients receiving ritonavir-boosted Invirase®.
ADRs Clinical Trials with ritonavir-boosted Invirase® include: Anaemia, diabetes mellitus, peripheral neuropathy, dysgeusia, acquired lipodystrophy, muscle spasms, decreased platelet count, increased blood amylase, increased blood bilirubin, increased blood creatinine.
ADRs reported in clinical trials with unboosted saquinavir include: Wasting syndrome, cyanosis, heart valve disorder, hypertension, hypotension, syncope, thrombophlebitis, hyperglycaemia, xerophthalmia, cheilitis, haemorrhoids, hepatomegaly, exacerbation of chronic liver disease with Grade 4 elevated liver function test, splenomegaly, thrombocytopenia, polyarthritis, convulsions, intracranial haemorrhage, poliomyelitis, leukoencephalopathy, seizures, acute myeloid leukaemia, confusional state, depression, vaginal discharge, abscess, angina tonsillaris, tumour, pneumonia, furunculosis, Stevens-Johnson syndrome, blepharitis, nephrolithiasis.
ADRs reported post-market (where saquinavir was taken as the sole protease inhibitor or in combination with ritonavir) include: Hypersensitivity, lipodystrophy (including loss of peripheral and facial subcutaneous fat, increased intraabdominal and visceral fat, breast hypertrophy and dorsicervical fat accumulation (buffalo hump)). - Sodium fusidate (Fucidin® tablet & IV infusion, Leo Pharma) New ADRs: Cholestasis, leukopenia, thrombocytopenia, pancytopenia, anaemia.
Leukopenia- Haematological disorders affecting the white cell line (neutropenia, granulocytopenia, agranulocytosis) are more rarely disorders affecting the other two cell lines have been reported, either as isolated events or associated events. This has been observed especially in case of treatment duration of more than 15 days and is reversible upon drug withdrawal.
Rhabdomyolysis may be fatal. - Trimebutine (Debridat®, Pfizer) Special warnings & precautions (for oral suspension): The administration of this product does not dispense with the need for the specific treatment of other anal diseases. Treatment must be short-term. If the symptoms are not relieved rapidly, a proctological examination must be carried out and the treatment reviewed.
New ADRs: Presyncope, syncope, skin reaction. - Vigabatrin (Sabril®, sanofi-aventis) Special warnings & precautions: A worsening of the visual field defect (VFD) after treatment discontinuation cannot be ruled out.
Study showed a possible relationship between the risk of visual field defects and the extent of vigabatrin exposure, in terms of daily dose (from 1 g to more than 3 g) and duration of treatment (maximum during the first three years).
Cases of cerebral abnormalities detected on MRI have been reported, particularly in young children treated for infantile spasms with high doses of vigabatrin. To date, the clinical consequences of these abnormalities are not known.
Abnormal movements including dystonia, dyskinesia and hypertonia have been reported in patients treated for infantile spasms. The benefit/risk ratio of vigabatrin must be evaluated for each patient. If new abnormal movements occur during treatment, dose reduction or gradual treatment discontinuation may be considered.
New ADRs: Speech disorder; cerebral abnormalities detected on MRI; abnormal movements including dystonia, dyskinesia and hypertonia (in association with MRI abnormalities).
Pregnancy: The risk of congenital abnormalities is increased 2 to 3 fold in children whose mothers were treated with an antiepileptic. The most frequently reported defects are cleft lip, cardiovascular and neural tube defects.
Polytherapy with antiepileptic drugs may be associated with a higher risk of congenital malformation than monotherapy.
Appropriate advice should be given to all women wishing to become pregnant or of childbearing age. The need for antiepileptic treatment must be re-evaluated when a patient is considering pregnancy. - Zoledronic acid (Zometa®, Novartis) Special warnings & precautions: 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 Zometa®-treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of Zometa® 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. Reports of atypical femoral fracture have been received in patients treated with Zometa®; however causality with Zometa® therapy has not been established.
During Zometa® 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.
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November 2011
- Cetirizine (Zyrtec®, GSK) Warnings & precautions: The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation. It is recommended to use a paediatric formulation of cetirizine.
Due to sorbitol in the formulation, the oral solution is not recommended in children aged less than 2 years.
Interaction: Allergy skin tests are inhibited by antihistamines and a wash-out period of 3 days is recommended before performing them.
New ADRs reported post-market: Amnesia, memory impairment. - Ciprofloxacin (Cirok®, Ziwell; Viprolox®, Zyfas) Warnings & precautions: Caution should be taken when using fluoroquinolones, including ciprofloxacin, in patients with known risk factors for prolongation of the QT interval such as congenital long QT syndrome, concomitant use of drugs that are known to prolong the QT interval (e.g. class IA and III antiarrythmics, tricyclic antidepressants, macrolides, antipsychotics), uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia), elderly, cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
Interactions: Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics).
New ADRs: Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), prolonged ECG QT. - Dactinomycin (Lyovac Cosmegen®, Invida) New ADR: Sepsis (including neutropenic sepsis) with fatal outcome.
- Daptomycin (Cubicin®, AstraZeneca) Special warnings & precautions: Anaphylaxis/hypersensitivity reactions have been reported with the use of antibacterial agents, including Cubicin®. If an allergic reaction to Cubicin® occurs, discontinue the drug and institute appropriate therapy.
Cubicin® should not be used for the treatment of pneumonia. It has been demonstrated in clinical studies that Cubicin® is not effective in the treatment of community-acquired pneumonia, due to binding to pulmonary surfactant and consequent inactivation.
It is recommended that in patients who receive Cubicin®, creatine phosphokinase (CPK) levels should be measured at baseline and at regular intervals (at least weekly), and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor or in whom elevations in CPK occur during treatment with Cubicin®. In patients with renal impairment, both renal function and CPK should be monitored more frequently than once weekly.
Physicians should be alert to signs and symptoms of peripheral neuropathy in patients receiving Cubicin®.
Eosinophilic pneumonia has been reported in patients receiving Cubicin®. In reported cases associated with Cubicin®, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. In general, patients developed eosinophilic pneumonia 2 to 4 weeks after starting Cubicin® and improved when Cubicin® was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Cubicin® should undergo prompt medical evaluation, and Cubicin® should be discontinued immediately. Treatment with systemic steroids is recommended.
Patients with persisting or relapsing Staphylococcus aureus bacteraemia/endocarditis or poor clinical response should have repeat blood cultures. False prolongation of prothrombin time (PT) and elevation of International Normalized Ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilized for the assay.
New ADRs include: Supraventricular arrhythmia, supraventricular tachycardia, vertigo, glossitis, increased blood creatinine, electrolyte imbalance, myositis, taste disorder, hypoaesthesia, anxiety, renal insufficiency, vaginitis, urticaria.
New ADRs reported post-market: Clostridium difficile-associated diarrhoea, infusion reactions including tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste; increased myoglobin, peripheral neuropathy, cough, eosinophilic pneumonia, vesiculobullous rash with or without mucous membrane involvement.
Hypersensitivity, manifested by isolated spontaneous reports including, but not limited to angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), pulmonary eosinophilia, vesiculobullous rash with mucous membrane involvement and sensation of oropharyngeal swelling, has been reported post-market.
Pregnancy & lactation: Reproductive and teratology studies performed in rats and rabbits at doses of up to 75mg/kg (2 and 4 times the 6mg/kg human dose, respectively, on a body surface area basis) revealed no evidence of harm to the foetus due to daptomycin. Daptomycin can cross the placenta in pregnant rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Cubicin® should be used during pregnancy only if the potential benefit outweighs the possible risk.
Excretion of daptomycin into milk of lactating animals has not been studied. In a single human case study, Cubicin® was administered daily for 28 days to a nursing mother at an IV dose of 500mg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 μg/mL, which is a low concentration. Until more experience is gained, women should be instructed to avoid breast-feeding while receiving Cubicin®.
Special populations: Safety and effectiveness of Cubicin® in patients under the age of 18 have not been established.
Daptomycin is eliminated primarily by the kidneys; therefore, an adjustment of Cubicin® dosage interval is recommended for patients with CrCl <30ml/min, including patients receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In patients with renal impairment, monitor both renal function and CPK more frequently than once weekly. - Estradiol (Estraderm® MX, Novartis) Warnings & precautions: Cases of anaphylactic/anaphylactoid reactions, which developed anytime during the course of Estraderm® treatment and required emergency medical management, have been reported in the post-marketing setting. Involvement of skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) has been noted. Angioedema involving the eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles and fingers) with or without urticaria requiring medical intervention has occurred in the post-marketing experience of using Estraderm®. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop angioedema after treatment with Estraderm® should not receive Estraderm® again.
New ADRs: Anaphylactic reaction, angioedema. - Etoricoxib (Arcoxia®, MSD) New ADR reported post-market: Hepatic failure.
- Fluvoxamine (Faverin®, Abbott) Contraindication: Fluvoxamine immediate-release tablets should not be used in combination with ramelteon.
Interaction: When twice daily, 100mg immediate-release fluvoxamine maleate tablets were administered for 3 days prior to single-dose co-administration of ramelteon 16mg and immediate-release fluvoxamine maleate tablets, the AUC for ramelteon increased approximately 190-fold and the Cmax increased approximately 70-fold compared to ramelteon administered alone.
New ADRs: Hyperprolactinaemia, pollakiuria, menstrual disorders e.g. amenorrhoea, hypomenorrhoea, metrorrhagia, menorrhagia.
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). The mechanism leading to this risk is unknown.
Pregnancy: Epidemiological data has suggested that the use of SSRI 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. - Hepatitis A vaccine (VAQTA®, MSD) Precautions: Use caution when vaccinating latex-sensitive individuals since the vial stopper and the syringe plunger stopper and tip cap contain dry natural latex rubber that may cause allergic reactions.
- Insulin glulisine (Apidra®, sanofi-aventis) Special warnings & precautions: Medication errors have been reported in which other insulins, particularly long-acting insulins, have been accidentally administered instead of insulin glulisine. Insulin label must always be checked before each injection to avoid medication errors between insulin glulisine and other insulins.
- Leflunomide (Arava®, sanofi-aventis) Special warnings & precautions: Interstitial lung disease has been reported rarely during treatment with leflunomide. The risk of its occurrence is increased in patients with a history of interstitial lung disease.
- Lincomycin (Lincocin® injection, Pfizer) Warnings & precautions: Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including lincomycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
Prescribing Lincocin® in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. - Maraviroc (Celsentri®, GSK) Special warnings & precautions: A case of possible Celsentri® induced hepatotoxicity and hepatic failure with allergic features has been reported in a study in healthy volunteers. There were fewer cases of hepatobiliary disorders reported in treatment-naïve patients on maraviroc than with efavirenz but the overall incidence of hepatic adverse events and ACTG (Adult Clinical Trials Group) Grade 3/4 liver function test abnormalities in treatment-naïve patients was similar between maraviroc and efavirenz.
- Norfloxacin (Bexinor®, Beacons Pharmaceuticals; Foxgoria®, Advanced Medi Mart);
- Ofloxacin (Flovid®, Goldplus Universal)
Warnings & precautions: Caution should be taken when using fluoroquinolones, including norfloxacin and ofloxacin, in patients with known risk factors for prolongation of the QT interval such as congenital long QT syndrome, concomitant use of drugs that are known to prolong the QT interval (e.g. class IA and III antiarrythmics, tricyclic antidepressants, macrolides, antipsychotics), uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia), elderly, cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
Fluoroquinolones, including norfloxacin and ofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid norfloxacin and ofloxacin in patients with a known history of myasthenia gravis.
Interactions: Norfloxacin and ofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. class IA and III antiarrythmics, tricyclic antidepressants, macrolides, antipsychotics).
New ADRs: Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), prolonged ECG QT, exacerbation of myasthenia gravis. - Pegfilgrastim (Neulastim®, Roche) Warnings & precautions: Physicians should exercise caution when considering the use of Neulastim® in patients with sickle cell disease, and only after careful evaluation of the potential risk and benefits.
Undesirable effects: Reactions of cutaneous vasculitis have been reported post-market in patients with cancer receiving Neulastim® (estimated reporting rate: 0.00038%). - Saxagliptin (Onglyza®, Bristol-Myers Squibb) Contraindication: History of a serious hypersensitivity reaction, such as anaphylaxis or angioedema, to any DPP4 (dipeptidyl peptidase 4) inhibitor.
Special warnings & precautions: During post-marketing experience, serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with use of saxagliptin. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency. If a serious hypersensitivity reaction to saxagliptin is suspected, discontinue Onglyza®, assess for other potential causes for the event, and institute alternative treatment for diabetes.
Undesirable effects: Onglyza® 2.5mg was compared to placebo in a 12-week trial in 170 patients with type 2 diabetes and moderate or severe renal impairment or end-stage renal disease (ESRD). The incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between Onglyza® and placebo.
In the active-controlled trial comparing add-on therapy with Onglyza® 5mg to glipizide in patients inadequately controlled on metformin alone, the incidence of reported hypoglycaemia was 3% (19 events in 13 patients) with Onglyza® 5mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycaemia (accompanying fingerstick blood glucose ≤50mg/dL) was reported in none of the Onglyza®-treated patients and in 35 glipizide-treated patients (8.1%) (p<0.0001).
During 12 weeks of treatment in patients with moderate or severe renal impairment or ESRD, the overall incidence of reported hypoglycaemia was 20% among patients treated with Onglyza® 2.5mg and 22% among patients treated with placebo. Four Onglyza®-treated patients (4.7%) and three placebo-treated patients (3.5%) reported at least one episode of confirmed symptomatic hypoglycaemia (accompanying fingerstick glucose ≤50 mg/dL).
In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 saxagliptin-treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with saxagliptin until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of saxagliptin that remained stable throughout saxagliptin treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There has been no spontaneous reports of tuberculosis associated with saxagliptin use. Causality has not been estimated and there are too few cases to date to determine whether tuberculosis is related to saxagliptin use.
There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in a saxagliptin-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin therapy. There has been no spontaneous reports of opportunistic infections associated with saxagliptin use.
During post-marketing experience, the following adverse reactions have been reported with use of saxagliptin: hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency. - Sertraline (Zoloft®, Pfizer) Special warnings & precautions: Selective Serotonin Reuptake Inhibitors (SSRIs) including sertraline may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, especially in pre-disposed patients. Sertraline should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.
New ADRs reported post-market: Cerebrovascular spasm (including reversible cerebral vasconstriction syndrome and call-fleming syndrome), akathisia, dystonia. - Terbutaline (Dhatalin®, DHA) Contraindication: Oral terbutaline sulfate is contraindicated in the treatment of acute or maintenance tocolysis.
Precautions: There are no adequate and well-controlled studies of terbutaline sulfate in pregnant women.
Published animal studies show that rat offspring exhibit alterations in behaviour and brain developement, including decreased cellular proliferation and differentation when dams were treated subcutaneously with terbutaline during the late stage of pregnancy and lactation period. Terbutaline exposures in rat dams were approximately 6.5 times the common human dose in adults of 15 mg/day, on a mg/m² basis.
Oral tebutaline sulfate has not been approved and should not be used for acute or maintenance tocolysis. In particular, terbutaline sulfate should not be used for tocolysis in the outpatient or home setting. Serious adverse reactions, including death, have been reported after administration of terbutaline sulfate to pregnant women. In the mother, these adverse reactions include increased heart rate, transient hyperglycaemia, hypokalaemia, cardiac arrhythmias, pulmonary oedema and myocardial ischaemia. Increased foetal heart rate and neonatal hypoglycaemia may occur as a result of maternal administration.
Terbutaline sulfate should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
- Venlafaxine (Efexor® XR, Pfizer) Special warnings: As with other serotonergic agents, the development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions may occur with venlafaxine treatment, particularly with concomitant use of other serotonergic drugs (including SSRIs, SNRIs and triptans), with drugs that impair metabolism of serotonin (including MAOIs, e.g. methylene blue), or with antipsychotics or other dopamine antagonists.
Interactions: As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, lithium, sibutramine, tramadol, or St. John's Wort [Hypericum perforatum]), with drugs which impair metabolism of serotonin (such as MAOIs, including linezolid, [an antibiotic which is a reversible non-selective MAOI], and methylene blue), or with serotonin precursors (such as tryptophan supplements). - Zoledronic acid (Aclasta®, Novartis) Contraindication: Severe renal impairment with CrCl <35ml/min.
Special warnings & precautions: The use of Aclasta® in patients with severe renal impairment (CrCl <35ml/min) is contraindicated due to an increased risk of renal failure in this population.
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October 2011
- Agomelatine (Valdoxan®, Servier) Special warnings & precautions: Valdoxan® should be used with caution in patients with a history of bipolar disorder, mania or hypomania and should be discontinued if a patient develops manic symptoms.
Caution should be exercised when Valdoxan® is administered to patients with pretreatment elevated transaminases (> the upper limit of the normal ranges and ≤3 times the upper limit of the normal range), preferably by laboratory tests within the first 3 weeks of treatment.
Caution should be exercised when prescribing Valdoxan® for patients with hepatic injury risk factors e.g. obesity/overweight/non-alcoholic fatty liver disease, substantial alcohol intake or concomitant medicinal products associated with risk of hepatic injury.
New ADRs: Aggression, nightmares, abnormal dreams. - Calcitonin (Miacalcic® nasal spray, Novartis) New ADR reported post-market: Tremor.
- Ciprofloxacin (C-flox®, Apotheca; Ciprofloxacin-Teva®, Dynamed; Ciprolet® & Qupron®, Zyfas; Enoxin®, CCM Pharmaceuticals; Ginorectol®, DHA; Topistin®, DHA) Special warnings & precautions: Caution should be taken when using fluoroquinolones, including ciprofloxacin, in patients with known risk factors for prolongation of the QT interval such as congenital long QT syndrome, concomitant use of drugs that are known to prolong the QT interval (e.g. class IA and III antiarrythmics, tricyclic antidepressants, macrolides, antipsychotics), uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia), elderly, cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
Interactions: Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics).
New ADRs: Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), prolonged ECG QT. - Clozapine (Clozaril®, Novartis) Pregnancy: Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
Antipsychotic drugs, including Clozaril®, should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. - Dasatinib (Sprycel®, Bristol-Myers Squibb) Warnings & precautions: Pulmonary arterial hypertension (PAH), confirmed by right heart catheterization, has been reported in association with Sprycel® treatment in post-marketing reports. In these cases, PAH was reported after initiation of Sprycel® therapy, including after more than one year of treatment. Patients with PAH reported during Sprycel® treatment were often taking concomitant medications or had co-morbidities in addition to the underlying malignancy.
Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating Sprycel® therapy. Patients who develop dyspnoea and fatigue after initiation of therapy should be evaluated for more common etiologies including pleural effusion, pulmonary oedema, anaemia, or lung infiltration. During this evaluation, guidelines for nonhaematologic adverse reactions should be followed. If the adverse reaction is severe, treatment must be withheld until the event has resolved or improved. If no alternative diagnosis is found, the diagnosis of PAH should be considered. If PAH is confirmed, Sprycel® should be permanently discontinued. Follow up should be performed according to standard practice guidelines. Improvements in haemodynamic and clinical parameters have been observed in Sprycel®-treated patients with PAH following cessation of Sprycel® therapy.
Adverse reactions: Pulmonary arterial hypertension (PAH), confirmed by right heart catheterization, has been reported in association with dasatinib exposure in post-marketing reports. In these cases, PAH was reported after initiation of dasatinib therapy, including after more than one year of treatment. Patients with PAH reported during dasatinib treatment were often taking concomitant medications or had co-morbidities in addition to the underlying malignancy. Improvements in haemodynamic and clinical parameters have been observed in patients with PAH following discontinuation of dasatinib.
Adverse reactions e.g. pleural effusion, ascites, pulmonary oedema and pericardial effusion with or without superficial oedema may be collectively described as “fluid retention”. Other fluid retention adverse reactions reported in patients taking Sprycel® were superficial localised oedema (9%), and generalised oedema (2%). Congestive heart failure/cardiac dysfunction, pericardial effusions, pulmonary hypertension and pulmonary oedema were also reported in < 2% of patients. - Desogestrel, ethinylestradiol (Mercilon®, Schering-Plough) Contraindications: Known predisposition for venous or arterial thrombosis, such as Activated Protein C (APC) resistance, antithrombin-III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia, and antiphospholipid antibodies.
Special warnings & precautions: A relationship between COC use and clinical hypertension has not been established.
(Hereditary) angioedema has been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive.
Mercilon® contains < 80 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on lactose-free diet should take this amount into consideration.
Prior to the initiation or reinstitution of Mercilon® a complete medical history (including family history) should be taken and pregnancy must be ruled out.
Interactions: Interactions can occur with drugs that induce microsomal enzymes, which can result in increased clearance of sex hormones. Maximal hepatic enzyme induction is generally not seen for 2-3 weeks but may then be sustained for at least 4 weeks after the cessation of drug therapy.
In case of long-term treatment with microsomal enzyme-inducing drugs another method of contraception should be considered.
Oral contraceptives may affect the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).
- Dexamethasone (Roximeth®, CCM Pharmaceuticals) Warnings & precautions: In patients on corticosteroid therapy subjected to unusual stress (from trauma or infection), increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated.
Drug induced secondary adrenocortical sufficiency may result from too rapid withdrawal of corticosteroids and may be minimised by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, corticosteroid therapy may need to be restarted. If the patient is receiving steroids already, dosage may have to be increased.
During prolonged corticosteroid therapy, adrenal suppression and atrophy may occur and secretion of corticotrophin may be suppressed. Abrupt withdrawal of corticosteroid therapy may precipitate acute adrenal insufficiency with muscle weakness, hypotension, hypoglycaemia, headache, nausea, vomiting, restlessness and muscle and joint pain. Muscle weakness and stiff joints may persist for three to six months after discontinuation of treatment. In some cases, withdrawal symptoms may stimulate a clinical relapse of the disease for which the patient has been under treatment. Duration of treatment and dosage appear to be important factors in determining suppression of the pituitary adrenal axis and response to stress on cessation of steroid treatment. The patient's liability to suppression is also variable. Some patients may recover normal function rapidly. In others, the production of hydrocortisone in response to the stress of infections, surgical operations or accident may be insufficient, and death results. Therefore, withdrawal of corticosteroids should always be gradual.
Corticosteroids may mask some signs of infection (such as fever and inflammation), and new infections may appear during their use. There may be decreased resistance and inability to localise infection when corticosteroids are used. Susceptibility to infection is not specific for any particular bacterial or fungal pathogen. Appropriate anti-microbial therapy should accompany glucocorticoid therapy when necessary e.g. in tuberculosis and viral and fungal infections of the eye. Patients who are on immunosuppressant drugs are more susceptible to infections. Chickenpox and measles, for example, can have a more serious or even fatal course in children on immunosuppressant corticosteroids. In such patients who have not had these diseases, particular care should be taken to avoid exposure. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.
Prolonged use of corticosteroids may produce posterior subcapsular cataracts or glaucoma with possible damage to optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. During long courses of treatment, laboratory and metabolic studies should be made. Fluid retention should be watched for via a fluid balance chart and daily weighing.
Sodium intake may need to be reduced to less than 1 g daily and potassium supplements may be necessary.
Use with caution in patients with impaired hepatic function, a reduction of dosage may be necessary. In treating chronic active liver disease with the drug, major adverse reactions such as vertebral collapse, diabetes, hypertension, cataracts and Cushing's syndrome occur in about 30% of patients.
Caution is recommended for elderly patients as they are more susceptible to adverse reactions.
The possibility of development of osteoporosis should be an important consideration in initiating and managing corticosteroid therapy, especially in postmenopausal women.
Caution should be taken in patients with diabetes mellitus.
Patients should not be vaccinated with live vaccines while on corticosteroid therapy. Other immunisation procedues should not be undertaken in patients on corticosteroid therapy, especially on high doses, because of possible hazards of neurological complications and lack of antibody response.
Close observation is necessary in patients with latent tuberculosis or tuberculin reactivity as reactivation of the disease may occur.
Chemoprophylaxis is indicated during prolonged corticosteroid therapy.
Particular care is required when considering the use of systemic corticosteroids in patient with the following conditions and frequent patient monitoring is necessary:
- Osteoporosis (postmenopausal females are particularly at risk).
- Hypertension or congestive heart failure.
- Existing or previous history of severe affective disorders (especially previous steroid psychosis).
- Diabetes mellitus (or a family history of diabetes).
- History of tuberculosis.
- Glaucoma (or a family history of glaucoma).
- Previous corticosteroid-induced myopathy.
- Liver failure.
- Renal insufficiency.
- Hypothyroidism.
- Epilepsy.
- Peptic ulceration.
- Migraine.
- Certain parasitic infestations in particular amoebiasis.
- Incomplete natural growth since glucocorticoids on prolonged administration may accelerate epiphyseal closure.
Children on long-term steroids must be carefully observed for potential serious adverse reactions such as obesity, growth retardation, osteoporosis and adrenal suppression.
New ADRs include: Amenorrhoea, weight gain, increased appetite, opportunistic infections, recurrence of dormant tuberculosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, papilloedema, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal diseases, acute pancreatitis, oesophageal ulceration and candidiasis, telangiectasia, anaphylaxis, leucocytosis, thromboembolism, myocardial rupture following recent myocardial infarction; psychological dependence.
A wide range of psychiatric reactions including affective disorders (e.g. irritable, depressed and labile mood, and suicidal thoughts), psychotic reactions (including mania, delusions, hallucinations, and aggravation of schizophrenia), behavioural disturbances, irritability, anxiety, sleep disturbances, and cognitive dysfunction including confusion and amnesia have been reported. Reactions are common and may occur in both adults and children. In adults, the frequency of severe reactions has been estimated to be 5-6%. Psychological effects have been reported on withdrawal of corticosteroids; the frequency is unknown.
Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death.
A 'withdrawal syndrome' may also occur including fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.
Pregnancy: In animal experiments, corticosteroids have been found to cause malformations of various kinds (cleft palate, skeletal malformations) and abortion. These findings do not seem to be relevant to humans. Reduced placental and birth weight have been recorded in animals and humans after long-term treatment. Since the possibility of suppression of the adrenal cortex in the newborn baby after long-term treatment must be considered, the needs of the mother must be carefully weighed against the risk to the foetus when prescribing corticosteroids.
- Drospirenone, ethinylestradiol (Yasmin®, Bayer) Special warnings & precautions: A large, prospective 3-armed cohort study has shown that the frequency of venous thromboembolism (VTE) diagnosis ranges between 8 to 10 per 10,000 woman years in low estrogen dose (< 50 µg ethinylestradiol) combined oral contraceptive (COC) users. The most recent data suggest that the frequency of VTE diagnosis is approximately 4.4 per 10,000 woman years in non-pregnant non-COC users, and ranges between 20 to 30 per 10,000 pregnant women or post partum. The incidence of VTE in women with or without other risk factors for VTE who used ethinylestradiol/drospirenone 0.03 mg/3 mg is in the same range as that for users of levonorgestrel-containing COCs and other COCs (various other COC brands). This has also been confirmed in a prospective, controlled, database study comparing users of ethinylestradiol 0.03 mg/drospirenone 3 mg to other COC users showing similar incidence of VTE among the cohorts.
The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. A COC should not be prescribed in case of a negative risk benefit assessment.
A complete medical history and physical examination should be taken prior to the initiation or reinstitution of COC use, guided by the contraindications and warnings, and should be repeated periodically. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of a COC. The frequency and nature of these assessments should be based on established practice guidelines and be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology.
Women should be advised that oral contraceptives do not protect against HIV (human immunodeficiency virus) infections (AIDS-acquired immunodeficiency syndrome) and other sexually transmitted diseases.
The efficacy of COCs may be reduced in the event of e.g. missed tablets, gastro-intestinal disturbances during tablet taking or concomitant medication.
With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.
If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
In some women withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken according to the directions, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.
New ADRs: Emotional lability, depression, loss of libido, unscheduled uterine bleeding, genital tract bleeding not further specified, venous and arterial thromboembolic events (peripheral deep venous occlusion, thrombosis and embolism/pulmonary vascular occlusion, thrombosis, embolism and infarction/myocardial infarction/cerebral infarction and stroke not specified as haemorrhagic).
Adverse reactions reported in women using COCs include:
- The frequency of diagnosis of breast cancer is very slightly increased among OC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown.
- Liver tumours (benign and malignant)
- Erythema nodosum
- Women with hypertriglyceridemia (increased risk of pancreatitis when using COCs)
- Occurrence or deterioration of conditions for which association with COC use is not conclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss
- Changes in glucose tolerance or effect on peripheral insulin resistance
- Crohn's disease, ulcerative colitis
Other side effects that had been reported with the use of COCs include: Hypoacusis, contact lens intolerance, breast secretion, vaginal moniliasis, vaginitis, breast hypertrophy, asthma, acne, eczema, hypotension.
Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers, some antibiotics) with oral contraceptives. - Econazole (Gyno-Pevaryl®, J & J) New ADR reported post-market: Hypersensitivity.
- Enfuvirtide (Fuzeon®, Roche) Undesirable effects: An increased rate of bacterial pneumonia was observed in subjects treated with Fuzeon® in the Phase 3 clinical trials compared to the control arm. The incidence of pneumonia was 2.7% or 3.2 events/100 patient-years in subjects receiving Fuzeon®+ background regimen. On analysis of all diagnoses of pneumonia (pneumonia, bacterial pneumonia, bronchopneumonia, and related terms) in pooled studies T20-301 and T20-302, an increased rate of bacterial pneumonia was observed in subjects treated with Fuzeon® compared to the control arm (6.9%, 6.7 pneumonia events per 100 patient-years versus 0.6 events per 100 patient-years, respectively). Approximately half of the study subjects with pneumonia required hospitalization. Three subject deaths in the Fuzeon® arm were attributed to pneumonia; all three had serious concomitant AIDS (acquired immunodeficiency syndrome)-related illnesses that contributed to their deaths. Risk factors for pneumonia included low initial CD4 (cluster of differentiation 4) lymphocyte count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease.
Because it was unclear whether the higher incidence rate of pneumonia was related to Fuzeon® use, an observational study in 1850 HIV (human immunodeficiency virus)-infected patients (740 Fuzeon® treated patients and 1110 non-Fuzeon® treated patients) was conducted to evaluate the risk of pneumonia in patients treated with Fuzeon®. A total of 123 patients had a confirmed or probable pneumonia event in this study (62 in the Fuzeon® treatment arm with 1962 patient-years of observation and 61 in the non-Fuzeon® treatment arm with 3378 patient-years of observation). The incidence of pneumonia was 3.2 events/100 patient-years in the Fuzeon® treatment arm and 1.8 events/100 patient-years in the non-Fuzeon® treatment arm. The hazard ratio, adjusting for other baseline risk factors, was 1.34 (95% C.I. = 0.90 – 2.00). Based on this observational study, it is not possible to exclude an increased risk of pneumonia in patients treated with Fuzeon® compared to non-Fuzeon® treated patients.
It is unclear if the increased incidence of pneumonia was related to Fuzeon® use. However, because of these finding, patients with HIV-1 infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia. Risk factors for pneumonia included low initial CD4 cell count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease.
- Fluticasone (Avamys® nasal spray, GSK) New ADR reported post-market: Headache.
- Human normal immunoglobulin (Kiovig®, Baxter Healthcare) Special warnings & precautions: Certain adverse reactions such as headache and flushing may be related to the rate of infusion.
Kiovig® is not indicated in patients with selective immunoglobulin A (IgA) deficiency where the IgA deficiency is the only abnormality of concern.
There is clinical evidence of an association between human immunoglobulin (IVIG) administration and thromboembolic events such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism and deep vein thrombosis which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin. Caution should be exercised in prescribing and infusion of IVIG in obese patients and in patients with pre-existing risk factors for thrombotic events such as a history of atherosclerosis, multiple cardiovascular risk factors, impaired cardiac output, hypercoagulable disorders.
Severe renal adverse reactions including acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis, have been reported in patients receiving IVIG therapy. In most cases, risk factors have been identified, such as sepsis or paraproteinaemia.
There have been reports of noncardiogenic pulmonary oedema (Transfusion Related Acute Lung Injury, TRALI) in patients administered IVIG (including Kiovig®).
An aseptic meningitis syndrome (AMS) has been reported to occur in association with IVIG (including Kiovig®) treatment. Discontinuation of IVIG treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to 2 days following IVIG treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL.
AMS may occur more frequently in association with high-dose (2 g/kg) IVIG treatment.
Haemolytic anaemia can develop subsequent to IVIG (including Kiovig®) therapy. IVIG products can contain blood group antibodies that may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, haemolysis.
New ADRs: Aseptic meningitis, haemolysis, transient ischaemic attack, tremor, deep vein thrombosis, hypotension, pulmonary embolism, pulmonary oedema, dyspnoea, abdominal pain, hyperhidrosis, chest pain, chills, transfusion-related acute lung injury.
Pregnancy: Maternally administered IVIG products have been shown to cross the placenta, increasingly during the third trimester.
- Isotretinoin (Roaccutane®, Roche) Undesirable effects: Serious cases of rhabdomyolysis, often leading to hospitalization, have been reported, particularly in those undertaking vigorous physical activity. None of the cases was associated with renal failure. All cases recovered.
- Levothyroxine (Euthyrox®, Merck) Interactions: Protease inhibitors (e.g. ritonavir, indinavir, lopinavir) may influence the effect of levothyroxine. Close monitoring of thyroid hormone parameters is recommended. If necessary, the levothyroxine dose has to be adjusted.
Phenytoin may influence the effect of levothyroxine by displacing levothyroxine from plasma proteins resulting in an elevated free thyroxine (fT4) and free triiodothyronine (fT3) fraction. On the other hand, phenytoin increases the hepatic metabolisation of levothyroxine. Close monitoring of thyroid hormone parameters is recommended.
Levothyroxine may intensify the effect of anticoagulants by displacing them from plasma protein bounds, which may increase the risk of haemorrhage e.g. CNS or gastrointestinal bleeding, especially in elderly patients. Therefore, it is necessary to check the coagulation parameters regularly at the start of and during concomitant therapy.
Sevelamer may decrease levothyroxine absorption and tyrosine kinase inhibitors (e.g. imatinib, sunitinib) may decrease the efficacy of levothyroxine. Therefore, it is recommended that patients are monitored for changes in thyroid function at the start or end of concomitant treatment. If necessary, the levothyroxine dose has to be adjusted.
Carbamazepine can increase the hepatic clearance of levothyroxine.
New ADRs: Atrial fibrillation and extrasystoles.
In case of hypersensitivity to any of the ingredients of Euthyrox® allergic reactions, particularly of the skin, may occur. Cases of angioedema have been reported. - M-M-R® II + Varivax® vaccines (Proquad®, MSD) New ADR: Varicella (vaccine strain).
- Miconazole, hydrocortisone (Daktacort®, J & J) Special warnings & precautions: Because of its corticosteroid content, avoid long-term treatment with Daktacort®. Once the inflammatory symptoms have disappeared, treatment may be continued with Daktarin® (miconazole nitrate 20 mg/g) topical cream.
Severe hypersensitivity reactions, including anaphylaxis and angioedema, have been reported during treatment with miconazole topical formulations. If a reaction suggesting hypersensitivity or irritation should occur, the treatment should be discontinued.
New ADR: Irritability.
New ADRs reported post-market: Hypersensitivity, angioedema, urticaria, pruritus, skin inflammation, skin hypopigmentation, application site reaction.
Pregnancy: Miconazole has not been observed to be embryotoxic or teratogenic in animals. Corticosteroids are known to cross the placenta and consequently can affect the foetus. - Nateglinide (Starlix®, Novartis) Warnings & precautions: When a patient stabilised on any oral antidiabetic agent is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue oral antidiabetic treatment and replace it with insulin on a temporary basis.
Interactions: While a more prolonged effect with concomitant administration of CYP2C9 inhibitors (such as voriconazole and sulfinpyrazone) cannot be excluded, the effect is likely to cause hypoglycaemia with potent CYP2C9 inhibitors such as fluconazole or in patients known to be poor metabolizers (CYP2C9*3/*3 genotype) of substrates of CYP2C9 enzyme.
The hypoglycaemic action of oral antidiabetic agents may be potentiated by certain drugs, including anabolic hormones (e.g. methandrostenolone), guanethidine, gymnema sylvestre, glucomannan and thioctic acid. When these drugs are administered to or withdrawn from patients receiving nateglinide, the patient should be observed closely for changes in glycaemic control.
The hypoglycaemic action of oral antidiabetic agents may be reduced by certain drugs, including somatropin, somatostatin analogues (e.g. lanreotide, octreotide), rifampin, phenytoin and St John's wort. - Olmesartan medoxomil (Olmetec®, Pfizer) Interactions: In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
- Pegfilgrastim (Peglasta®, Kyowa Hakko Kirin) New ADRs: Erythema & flushing.
Cases of Sweet's syndrome (acute febrile dermatosis) have been reported post-market.
Reactions of cutaneous vasculitis have been reported post-market in patients with cancer receiving pegfilgrastim (estimated reporting rate: 0.00038%). - Ruscogenins, trimebutine (Proctolog®, Pfizer) Contraindication: Hypersensitivity to propylene glycol.
Special warnings & precautions: The administration of this product does not dispense with the need for the specific treatment of other anal diseases. Treatment must be short-term. If the symptoms are not relieved rapidly, a proctological examination must be carried out and the treatment reviewed.
New ADRs: Presyncope, syncope, skin reaction.
Pregnancy: As a precautionary measure, it is preferable not to use trimebutine during the first trimester of pregnancy. In the absence of any expected harmful effect for either mother or child, the use of trimebutine during the 2nd and 3rd trimesters of pregnancy should only be considered if it is necessary. - Sevoflurane (Sevorane®, Abbott) Contraindication: Sevoflurane should not be used in patients with known sensitivity to other halogenated agents.
Warnings & precautions: The concentration of sevoflurane being delivered from a vapourizer must be known exactly. As volatile anaesthetics differ in their physical properties, only vapourizers specifically calibrated for sevoflurane must be used. The administration of general anaesthesia must be individualized based on the patient's response.
Isolated cases of ventricular arrhythmia were reported in paediatric patients with Pompe's disease.
Caution should be exercised in administering general anaesthesia, including sevoflurane, to patients with mitochondrial disorders.
Lactation: It is not known whether sevoflurane or its metabolites is excreted in human milk. Due to the absence of documented experience, women should be advised to skip breastfeeding for 48 hours after administration of sevoflurane and discard milk produced during this period. - Strontium ranelate (Protos®, Servier) New ADRs: Insomnia, gastro-oesophageal reflux, dyspepsia, constipation, flatulence, hepatitis.
- Sunitinib (Sutent®, Pfizer) Special warnings & precautions: Haemorrhagic events including gastrointestinal, respiratory, tumour, urinary tract and brain haemorrhages, some of which were fatal, have been reported through post-marketing experience.
Cases of pulmonary haemorrhage, some with a fatal outcome, have been observed in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib for metastatic renal cell carcinoma (MRCC), gastrointestinal stromal tumour (GIST) and metastatic non-small cell lung cancer (NSCLC).
Treatment emergent bleeding events occurred in 18% of patients receiving sunitinib in the double-blind treatment phase of GIST Study compared to 17% of patients receiving placebo. In patients receiving sunitinib for treatment-naïve MRCC, 39% of patients had bleeding events compared with 11% of patients receiving interferon-alfa (IFN-alfa). Eleven (3.1%) patients on sunitinib versus 1 (0.3%) patient on IFN-alfa experienced Grade 3 or greater treatment-related bleeding events. Of patients receiving sunitinib for cytokine-refractory MRCC, 26% experienced bleeding.
Treatment-related hypertension was reported in approximately 30% of patients receiving sunitinib for treatment-naïve MRCC compared to 6% of patients receiving IFN-alfa. Severe hypertension occurred in 12% of treatment-naïve patients on sunitinib and <1% of patients on IFN-alfa.
Cases of fatal haemorrhage associated with thrombocytopenia were reported through post-marketing experience.
Cardiovascular events, including heart failure, cardiomyopathy, and myocardial disorders, some of which were fatal, have been reported through post-marketing experience.
Thirteen patients (3%) receiving sunitinib for treatment-naïve MRCC and four (2%) patients on the two cytokine-refractory MRCC studies had venous thromboembolic events reported. Nine of these patients had pulmonary embolism, one was Grade 2 and eight were Grade 4. Eight patients had deep venous thrombosis (DVT), one with Grade 1, two with Grade 2, four with Grade 3, and 1 with Grade 4. Dose interruption occurred in one of these cases. In treatment-naïve MRCC patients receiving IFN-alfa, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, all Grade 4.
Treatment-emergent acquired hypothyroidism was noted in 4% of GIST patients on sunitinib versus 1% on placebo. Hypothyroidism was reported as an adverse event in 16% of patients on sunitinib in the treatment-naïve MRCC study and three patients (<1%) in the IFN-alfa arm, and in 4% of patients across the two cytokine-refractory MRCC studies.
Pancreatitis was observed in 0.4% of patients with solid tumours.
Hepatotoxicity has been observed in patients treated with sunitinib. Cases of hepatic failure, some with a fatal outcome, were observed in <1% of solid tumour patients treated with sunitinib. Monitor liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels) before initiation of treatment, during each cycle of treatment, and as clinically indicated. Sunitinib should be interrupted for Grade 3 or 4 hepatic-related adverse events and discontinued if there is no resolution.
Cases of impaired wound healing have been reported during sunitinib therapy. Temporary interruption of sunitinib therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume sunitinib therapy following a major surgical intervention should be based upon clinical judgement of recovery from surgery.
Osteonecrosis of the jaw (ONJ) has been observed in clinical trials and has been reported in post-marketing experience in patients treated with sunitinib. The majority of cases occurred in patients who had received prior or concomitant treatment with intravenous (IV) bisphosphonates, for which ONJ is an identified risk. Caution should therefore be exercised when sunitinib and IV bisphosphonates are used either simultaneously or sequentially.
Invasive dental procedures are also an identified risk factor for ONJ. Prior to treatment with sunitinib, a dental examination and appropriate preventive dentistry should be considered. In patients being treated with sunitinib, who have previously received or are receiving IV bisphosphonates, invasive dental procedures should be avoided, if possible.
Cases of tumour lysis syndrome (TLS), some fatal, have been rarely observed in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib. Patients generally at risk of TLS are those with high tumour burden prior to treatment. These patients should be monitored closely and treated as clinically indicated.
New ADRs: Exfoliative dermatitis, periorbital oedema, lymphopenia, insomnia, depression, gastro-oesophageal reflux disease, skin discolouration, pruritus, skin lesion, skin reaction, influenza like illness, hair colour changes.
Treatment-related epistaxis, which was the most frequent haemorrhagic adverse event reported, occurred in 8% of patients with solid tumours.
In clinical studies of sunitinib, seizures have been observed in subjects with radiological evidence of brain metastases. In addition, there have been rare (<1%) reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None of these subjects had a fatal outcome to the event.
The infections observed most commonly with sunitinib treatment are infections typically seen in cancer patients, e.g. respiratory, urinary tract, skin infections and sepsis. Rare cases of necrotizing fasciitis, including of the perineum, sometimes fatal, have been reported post-market.
Rare cases of myopathy and/or rhabdomyolysis with or without acute renal failure, in some cases with fatal outcome, have been reported post-market. Most of these patients had pre-existing risk factors and/or were receiving concomitant medications known to be associated with these adverse reactions.
Cases of osteonecrosis of the jaw (ONJ) have been reported post-market in patients treated with sunitinib, most of which occurred in patients who had identified risk factors for ONJ, in particular exposure to IV bisphosphonates and/or a history of dental disease requiring invasive dental procedures.
Cases of renal impairment and/ or failure, in some cases with fatal outcome, have been reported post-market.
Pulmonary embolism and cardiomyopathy, in some cases with fatal outcome, have been reported post-market.
Cases of arterial thromboembolic events (ATE), sometimes fatal, have been reported post-market in patients treated with sunitinib. The most frequent events included cerebrovascular accident, transient ischaemic attack and cerebral infarction. Risk factors associated with ATE, in addition to the underlying malignant disease and age ≥ 65 years, included hypertension, diabetes mellitus, and prior thromboembolic disease.
Cases of tumour lysis syndrome (TLS) and pulmonary haemorrhage, some fatal, have been reported post-market in patients treated with sunitinib.
- Terbinafine (Lamisil®, Novartis) Interactions: Fluconazole increased the Cmax and AUC of terbinafine by 52% and 69% respectively, due to inhibition of both CYP2C9 and CYP3A4 enzymes. Similar increase in exposure may occur when other drugs which inhibit both CYP2C9 and CYP3A4 such as ketoconazole and amiodarone are concomitantly administered with terbinafine.
There was no effect of terbinafine on the pharmacokinetics of fluconazole. Further there was no clinically relevant interaction between terbinafine and the potential comedications cotrimoxazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline.
In studies in healthy subjects characterized as extensive metabolisers of dextromethorphan (antitussive drug and CYP2D6 probe substrate), terbinafine increased the dextromethorphan/dextrorphan metabolic ratio in urine by 16- to 97-fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolisers to poor metaboliser status.
New ADRs reported post-market: Photosensitivity reactions (e.g. photodermatosis, photosensitivity allergic reaction and polymorphic light eruption).
- Varicella virus vaccine (Varivax®, MSD) New ADR: Varicella (vaccine strain).
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September 2011
- Amlodipine (Norvasc® & Amloc®, Pfizer) Interactions: Grapefruit juice is known to inhibit the cytochrome P450 system, thereby affecting the pharmacokinetics of drugs such as calcium channel blockers. Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.
With concomitant use with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients, the plasma concentration of amlodipine increased. The clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors.
There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, hypericum perforatum (St John's Wort)) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers. - Aripiprazole (Abilify®, Bristol-Myers Squibb) Special populations: When concomitant administration of aripiprazole with strong CYP3A4 inhibitors such as ketoconazole or clarithromycin is indicated, the aripiprazole dose should be reduced to one-half of the usual dose.
When concomitant administration of aripiprazole with strong inhibitors of CYP3A4 (such as ketoconazole or clarithromycin) and CYP2D6 (such as quinidine, fluoxetine, or paroxetine) is indicated, the aripiprazole dose should be reduced to one-quarter (25%) of the usual dose. When the CYP3A4 and/or CYP2D6 inhibitor is withdrawn from the combination therapy, the aripiprazole dose should be increased.
Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g. a potent CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favourable clinical response.
The aripiprazole dose in poor metabolizers (PM) patients should initially be reduced to one-half (50%) of the usual dose and then adjusted to achieve a favorable clinical response. The dose of aripiprazole for PM patients who are administered a strong CYP3A4 inhibitor should be reduced to one-quarter (25%) of the usual dose. - Azithromycin (Zmax®, Pfizer) Special warnings & precautions: Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including Zmax®, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
Studies evaluating the use of repeated courses of azithromycin extended release granules have not been conducted.
Interactions: In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously.
Co-administration of azithromycin extended releases granules for oral suspension with a single 20ml dose of co-magaldrox (aluminium hydroxide and magnesium hydroxide) did not affect the rate and extent of azithromycin absorption.
New ADRs include: Pneumonia, fungal infection, bacterial infection, gastroenteritis, paraesthesia, dysgeusia, dyspnoea, epistaxis, osteoarthritis, dysuria, metrorrhagia, testicular disorder, increased blood alkaline phosphatase.
In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Azithromycin prolonged-release granules for oral suspension clinical trials:
- with an incidence of ≥ 1%: increased basophils, eosinophils, monocytes, and neutrophils; decreased bicarbonate; abnormal lymphocytes.
- with an incidence of < 1%: increased alanine aminotransferase, aspartate aminotransferase, bicarbonate, bilirubin, blood urea, chloride, creatinine, glucose, and platelets; decreased haematocrit; abnormal potassium, sodium, and white blood cell count.
Where follow-up was provided, changes in laboratory tests appeared to be reversible. - Basiliximab (Simulect®, Novartis) Warnings & precautions: Severe acute (less than 24 hours) hypersensitivity reactions have been observed both on initial exposure to Simulect® and on re-exposure to a subsequent course of therapy. These included anaphylactoid type reactions such as rash, wheezing, cardiac failure and capillary leak syndrome.
Transplant patients receiving immunosuppressive regimens involving combinations with or without Simulect® are at increased risk of developing lymphoproliferative disorders (LPDs) (such as lymphoma) and opportunistic infections (such as cytomegalovirus, CMV). In clinical trials, the incidence of opportunistic infections was similar in patients using immunosuppressive regimens with or without Simulect®. In a pooled analysis of two five-year extension studies, no differences were found in the incidence of malignancies and LPDs between immunosuppressive regimens with or without Simulect®.
No data is available on either the effects of live and inactive vaccination or the transmission of infection by live vaccines in patients receiving Simulect®. Nevertheless, live vaccines are not recommended for immunosuppressed patients. Inactivated vaccines may be administered to immunosuppressed patients; however, response to the vaccine may depend on the degree of the immunosuppression.
New ADRs reported post-market: Pruritus, dyspnoea, hypotension, tachycardia.
In a pooled analysis of two five-year extension studies the incidence and cause of death remained similar in both treatment groups (Simulect® 15%, placebo 11%), the primary cause of death being cardiac-related disorders such as cardiac failure and myocardial infarction (Simulect® 5%, placebo 4%). - Ciprofloxacin (Cycin®, Pharmaforte; Ciproctal®, DHA; Neofloxin®, Advanced Medi Mart) Warnings & precautions: Caution should be taken when using fluoroquinolones, including ciprofloxacin, in patients with known risk factors for prolongation of the QT interval such as congenital long QT syndrome, concomitant use of drugs that are known to prolong the QT interval (e.g. class IA and III antiarrythmics, tricyclic antidepressants, macrolides, antipsychotics), uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia), elderly, cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).
Interactions: Ciprofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics).
New ADRs: Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), prolonged ECG QT.
Neofloxin®: Isolated cases of tendon damage (especially in the elderly and those taking corticosteroids) have been reported. - Deferasirox (Exjade®, Novartis) Warnings & precautions: Exjade® is not recommended in patients with severe hepatic impairment (Child-Pugh C).
Interactions: In a healthy volunteer study, the concomitant administration of Exjade® (repeated dose of 30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase in theophylline AUC by 84% (90% CI: 73% to 95%). The single dose Cmax was not affected, but an increase of theophylline Cmax is expected to occur with chronic dosing. When Exjade® and theophylline are used concomitantly, monitoring of theophylline concentration and possible theophylline dose reduction should be considered. An interaction between Exjade® and other CYP1A2 substrates may be possible.
Special populations: Exjade® has been studied in a clinical trial in subjects with hepatic impairment. For patients with moderate hepatic impairment (Child-Pugh B), the starting dose should be reduced by approximately 50%. Exjade® should not be used in patients with severe hepatic impairment (Child-Pugh C). - Etoricoxib (Arcoxia®, MSD) New ADR reported post-market: Fixed drug eruption.
- Finasteride (Propecia® & Proscar®, MSD) New ADRs reported post-market: Erectile dysfunction that continued after discontinuation of treatment; male infertility and/or poor seminal quality- normalization or improvement of seminal quality has been reported after discontinuation of finasteride; depression.
Propecia®: Finasteride has been studied for prostate cancer risk reduction at 5 times the dosage recommended for male pattern hair loss. In a 7-year placebo-controlled trial that enrolled 18,882 healthy men, of whom 9060 had prostate needle biopsy data available for analysis, prostate cancer was detected in 803 (18.4%) men receiving finasteride 5 mg and 1147 (24.4%) men receiving placebo. In the finasteride 5 mg group, 280 (6.4%) men had prostate cancer with Gleason scores of 7-10 detected on needle biopsy vs. 237 (5.1%) men in the placebo group. Additional analyses suggest that the increase in the prevalence of high-grade prostate cancer observed in the finasteride 5 mg group may be explained by a detection bias due to the effect of finasteride 5 mg on prostate volume. Of the total cases of prostate cancer diagnosed in this study, approximately 98% were classified as intracapsular (clinical stage T1 or T2) at diagnosis. The clinical significance of the Gleason 7-10 data is unknown. - Fluticasone (Flixonase®, GSK) Warnings & precautions: Systemic effects with nasal corticosteroids have been reported, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations.
- Gadoxetic acid (Primovist®, Bayer) Special warnings & precautions: Particularly careful risk-benefit assessment is required in patients with known hypersensitivity to Primovist®.
As with other intravenous contrast agents, Primovist® can be associated with anaphylactoid/hypersensitivity or other idiosyncratic reactions characterized by cardiovascular, respiratory and cutaneous manifestations, and ranging to severe reactions including shock.
In patients with an allergic disposition the decision to use Primovist® must be made after particularly careful evaluation of the risk-benefit ratio.
Most of these reactions occur within half an hour of administration. Therefore, post-procedure observation of the patient is recommended.
Medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures are necessary.
Delayed reactions after hours up to several days have been rarely observed.
Patients taking beta-blockers who experience such reactions may be resistant to treatment with beta agonists.
Caution should be exercised when Primovist® is administered to patients with severe cardiovascular problems because only limited data are available so far.
In healthy subjects, gadoxetate disodium is equally eliminated via renal and hepatobiliary routes.
Prior to administration of Primovist®, it is recommended, that all patients are screened for renal dysfunction by obtaining a history and/or laboratory tests.
In patients with severely impaired renal function, the benefits must be weighed carefully against the risks, since contrast medium elimination is delayed in such cases. A sufficient period of time for elimination of the contrast agent from the body prior to any re-administration in patients with renal impairment should be ensured.
Gadoxetate disodium can be removed from the body by haemodialysis. About 30% of the administered dose is eliminated from the body by a single dialysis session of 3 hours starting 1 hour post injection. In end-stage renal failure patients, gadoxetate disodium was almost completely eliminated via dialysis and biliary excretion within the observation period of 6 days, the majority within 3 days.
There have been reports of nephrogenic systemic fibrosis (NSF)/nephrogenic fibrosing dermopathy (NFD) associated with the use of some contrast agents containing gadolinium in patients with acute or chronic severe renal impairment (GFR<30ml/min/1.73m2) and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.
As there is a possibility that NSF/NFD may occur with Primovist®, it should only be used in these patients if the benefits outweigh the risks.
There is no robust evidence to suggest that haemodialysis can prevent or treat the development of NSF but haemodialysis shortly after Primovist® administration in patients currently recently receiving haemodialysis may be useful at removing Primovist® from the body. There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis.
Intramuscular administration must be strictly avoided because it may cause local intolerance reactions including focal necrosis.
Interactions: Animal studies demonstrated that compounds belonging to the class of anionic medicinal products, e.g. rifampicin, block the hepatic uptake of Primovist® thus reducing the hepatic contrast effect. In this case, the expected benefit of an injection of Primovist® might be limited. No other interactions with other medicinal products are known from animal studies.
An interaction study in healthy subjects demonstrated that the co-administration of the OATP (organic anion-transporting polypeptide) inhibitor erythromycin did not influence efficacy and pharmacokinetics of Primovist®. No further clinical interaction studies with other medicinal products have been performed.
Elevated levels of bilirubin (>3mg/dl) or ferritin can reduce the hepatic contrast effect of Primovist®. If Primovist® is used in these patients, complete the magnetic resonance imaging no later than 60 minutes after Primovist® administration.
Serum iron determination using complexometric methods (e.g. Ferrocine complexation method) may result in falsely high or low values for up to 24 hours after the examination with Primovist® because of the free complexing agent caloxetate trisodium contained in the contrast medium solution.
New ADRs include: Dysgeusia, increased blood pressure, flushing, respiratory distress, generalized pruritus, eye pruritus, salivary hypersecretion, chest pain, injection site extravasation.
New ADRs reported post-market: Hypersensitivity/anaphylactoid reaction (e.g. shock, hypotension, pharyngolaryngeal oedema, urticaria, face oedema, rhinitis, conjunctivitis, abdominal pain, hypoaesthesia, sneezing, cough, pallor), restlessness, tachycardia.
The most serious ADR in patients receiving Primovist® is anaphylactoid shock. Life-threatening and/or fatal cases have been reported post-market.
The most frequently observed ADRs (≥ 0.5 %) in patients receiving Primovist® are nausea, headache, feeling hot, blood pressure increased and dizziness.
Delayed allergoid reactions (hours later up to several days) have been rarely observed.
Cases of nephrogenic systemic fibrosis (NSF) have been reported with some contrast agents containing gadolinium.
Slightly elevated serum iron and serum bilirubin values have been observed in less than 1% of patients after administration of Primovist®. However, the values did not exceed more than 2-3 times the baseline values and returned to their initial values without any symptoms within 1 to 4 days.
Pregnancy & lactation: Animal studies at clinically relevant doses have not shown reproductive toxicity afer repeated administration. The potential risk for humans is unknown. Primovist® should only be used during pregnancy if the clinical condition of the woman requires the use of gadoxetate disodium.
It is unknown whether gadoxetate disodium is excreted in human milk. There is evidence from non-clinical data that gadoxetate is excreted into breast milk in very small amounts (less than 0.5% of the dose intravenously administered) and the absorption via the gastrointestinal tract is poor (about 0.4% of the dose orally administered were excreted in the urine). At clinical doses, no effects on the infant are anticipated. Continuing or discontinuing breast feeding for a period of 24 hours after administration of Primovist® should be at the discretion of the doctor and lactating mother.
Special populations: Primovist® is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.
- Lithium (Camcolit®, Apex Pharma) Contraindications: Untreated or untreatable hypothyroidism; cardiac disease associated with rhythm disorder; low body sodium levels for example dehydrated patients, those on low sodium diets, or those with Addison's disease; severe Impaired renal function.
Warnings & precautions: Serum concentration of lithium should be measured on a sample taken just prior to the time when a dose of lithium is due to be taken (i.e. at trough level 12 hours following the last dose).
Toxic effects may be expected at serum-lithium concentrations of about 1.5 mmol/litre, although they can appear at lower concentrations. They call for immediate withdrawal of treatment and should always be considered very seriously.
Serum lithium concentrations should be monitored more frequently (revert to weekly monitoring) in the following circumstances:
- Dosage alteration or change of lithium formulation (bioavailability may differ)
- Significant intercurrent disease
- Intercurrent infection
- Significant change in sodium intake
- Significant change in fluid intake
- Treatment with drugs altering renal clearance of lithium
- Treatment with drugs likely to upset electrolyte balance.
Patients should also be warned to report if polyuria or polydipsia develops. Episodes of nausea and vomiting or other conditions leading to salt/water depletion (including severe dieting) should also be reported. Patients should be advised to maintain their usual salt and fluid intake.
Concomitant administration of antipsychotics should be avoided.
Lithium should be stopped 24 hours before major surgery, but the normal dose can be continued for minor surgery if fluids and electrolytes are carefully monitored.
Interactions: Co-administration of the following drugs with lithium may lead to increased lithium concentrations and a risk of toxicity:
- any drug which may cause renal impairment has the potential to cause lithium levels to rise, thereby causing toxicity. If the use of the drug is unavoidable, carefully monitor lithium blood level and adapt dosage as necessary.
- antibiotics (metronidazole, tetracyclines, co-trimoxazole, trimethoprim). Toxic symptoms may also occur at low or normal levels when used in conjunction with co-trimoxazole or trimethoprim; non-steroidal anti-inflammatory drugs including selective cyclo-oxygenase (COX) II inhibitors.
- drugs affecting the renin angiotensin system (ACE inhibitors, Angiotensin II receptor antagonists).
- diuretics (including herbal preparations). In addition to the effects noted above, thiazide diuretics show a paradoxical antidiuretic effect resulting in possible water retention and lithium intoxication. Loop diuretics e.g. furosemide and bumetanide, seem less likely to cause lithium retention, although caution is warranted.
- other drugs affecting electrolyte balance, e.g. steroids, may alter lithium excretion and should therefore be avoided.
Co-administration of the following drugs with lithium may lead to decreased lithium concentrations and a risk of loss of efficacy:
- xanthine derivatives (e.g. theophylline, caffeine).
- products containing large quantities of sodium e.g. sodium bicarbonate.
- carbonic anhydrase inhibitors.
- urea.
Concomitant use of the following drugs may precipitate symptoms of toxicity when the lithium level is within the normal range:
- antipsychotics, including the atypical antipsychotics olanzapine, clozapine and haloperidol at high doses.
- carbamazepine
- phenytoin
- methyldopa
- clonazepam
- tricyclic and tetracyclic antidepressants
- calcium channel blockers. These drugs may cause neurotoxic reactions at therapeutic levels.
- neuromuscular blocking agents. Lithium may cause neurotoxic reactions at therapeutic lithium levels.
Concurrent use of selective serotonin re-uptake inhibitors (SSRIs) with lithium may precipitate a serotonergic syndrome.
Monitor serum lithium concentrations more frequently if NSAID (non-steroidal anti-inflammatory drug) therapy including COX II inhibitors is initiated or discontinued.
Lithium toxicity reported is suggestive of serotonin syndrome when lithium is used with triptans.
Lithium can cause an increase in the QTc interval, particularly at higher blood levels. Therefore concurrent use of drugs which have a risk of prolonging the QTc interval should be avoided, and consideration be made of other potential risk factors such as increasing age, female sex, congenital long QT syndrome, cardiac and thyroid disease and the following metabolic disturbances: hypocalcaemia, hypokalaemia, hypomagnesaemia.
The following products have a high risk of causing QT prolongation and torsade de pointes: Class Ia antiarrhythmics , (disopyramide, procainamide, quinidine), Class III antiarrhythmics (amiodarone, sotalol), arsenic trioxide, artemisinin derivatives, dolasetron mesylate, mefloquine, IV erythromycin, amisulpride, haloperidol, , pimozide, sertindole, terfenadine, thioridazine.
ECG should be performed after initiation of treatment and at any point where the patient becomes symptomatic or when there are changes in disease or treatment which may increase the risk of interaction or arrhythmia.
Rapid reduction of sodium intake may cause raised lithium levels.
Intercurrent illness may cause lithium toxicity.
New ADRs include: Leucocytosis, hyperthyroidism, parathyroid adenoma, hyperglycaemia, coma, pseudotumour cerebri, syndrome of irreversible lithium effectuated neurotoxicity (SILENT), encephalopathy, stupor, seizures, neuroleptic malignant syndrome, myasthenia gravis, serotonin syndrome, parkinsonism, extrapyramidal symptoms, ataxia, memory impairment, nystagmus, hyperactive deep tendon reflexes, scotomata, cardiac arrest, ventricular fibrillation, ventricular tachycardia, ventricular arrhythmias, Torsade de pointes, QT interval prolongation, cardiomyopathy, arrhythmia, bradycardia, sinus node dysfunction, peripheral circulatory collapse, hypotension, acneiform eruptions, symptoms of nephrogenic diabetes insipidus, impairment of renal function, permanent changes in the kidney, nephrotic syndrome, histological renal changes with interstitial fibrosis after long term treatment; sexual dysfunction, sudden unexplained death.
Lithium salts have been implicated in dysgeusia.
Pregnancy & lactation: Lithium therapy should not be used during pregnancy, especially during the first trimester, unless considered essential. There is epidemiological evidence that it may be harmful to the foetus in human pregnancy. Lithium crosses the placental barrier. In animal studies lithium has been reported to interfere with fertility, gestation and foetal development. An increase in cardiac and other abnormalities, especially Ebstein anomaly, are reported. Therefore, a pre-natal diagnosis such as ultrasound and electrocardiogram examination is strongly recommended. In certain cases where a severe risk to the patient could exist if treatment were stopped, lithium has been continued during pregnancy.
If it is considered essential to maintain lithium treatment during pregnancy, serum lithium levels should be closely monitored and measured frequently since renal function changes gradually during pregnancy and suddenly at parturition. Dosage adjustments are required. It is recommended that lithium be discontinued shortly before delivery and reinitiated a few days post-partum.
Neonates may show signs of lithium toxicity necessitating fluid therapy in the neonatal period. Neonates born with low serum lithium concentrations may have a flaccid appearance that returns to normal without any treatment.
It is advisable that women treated with lithium should adopt adequate contraceptive methods. In case of a planned pregnancy, it is strongly recommended to discontinue lithium therapy.
Since adequate human data on use during lactation, adequate animal reproduction studies are not available and as lithium is secreted in breast milk, bottle-feeding is recommended.
- Methoxy polyethylene glycol-epoetin beta (Mircera®, Roche) Special warnings & precautions: Pure Red Cell Aplasia (PRCA) caused by anti-erythropoietin antibodies has been reported in association with Erythropoiesis-Stimulating Agents (ESAs) including Mircera®.
Undesirable effects: Neutralizing anti-erythropoietin antibody-mediated pure red cell aplasia (AEAB-PRCA) associated with Mircera® therapy has been reported post-market. With this exception, the safety information collected during post-marketing experience reflects the expected adverse event profile in these populations and the ADR profile of Mircera®. - Morphine (MST Continus®, Mundipharma) Contraindication: Acute abdomen.
Special warnings & precautions: As with all narcotics a reduction in dosage may be advisable in patients with significantly impaired renal or hepatic function.
Use with caution in patients with e.g. impaired respiratory function, convulsive disorders, acute alcoholism, delirium tremens, diseases of the biliary tract.
As with all morphine preparations, patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive MST Continus® tablets for 24 hours prior to the intervention.
There is potential for development of psychological dependence (addiction) to opioid analgesics, including morphine. The product should be used with particular care in patients with a history of alcohol and drug abuse.
It is not possible to ensure bio-equivalence between different brands of prolonged release morphine products. Therefore, it should be emphasised that patients, once titrated to an effective dose, should not be changed from MST Continus® preparations to other slow, sustained or prolonged release morphine or other potent narcotic analgesic preparations without retitration and clinical assessment.
A reduction in dosage may be advisable in the elderly.
MST Continus® is not recommended for use in children.
Interactions: Morphine sulphate potentiates the effects of tranquillisers, general anaesthetics, phenothiazines, other central nervous depressants including hypnotics or sedatives, alcohol, muscle relaxants, antihypertensives and gabapentin.
Morphine sulphate should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.
Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsons and anti-emetics, may interact with morphine sulphate to potentiate anticholinergic adverse events.
Plasma concentrations of morphine sulphate may be reduced by rifampicin.
Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine sulphate, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine sulphate, and may possibly decrease plasma concentrations of morphine sulphate.
New ADRs: Myoclonus, convulsions, visual disturbance, bradycardia, palpitations, tachycardia, hypertension, exacerbation of pancreatitis, hyperhidrosis, ureteric spasm, amenorrhoea, decreased libido, drug tolerance, drug withdrawal syndrome.
Pregnancy: MST Continus® tablets are not recommended during pregnancy and labour due to the risk of neonatal respiratory depression. - Nimodipine (Nimotop®, Bayer) Special warnings & precautions: In patients with unstable angina or within the first 4 weeks after acute myocardial infarction, physicians should consider the potential risk (e.g. reduced coronary artery perfusion and myocardial ischaemia) versus the benefit (e.g. improvement of brain perfusion).
- Omeprazole (Losec® & Losec® MUPS®, AstraZeneca);
- Pantoprazole (Controloc®, Hyphens Marketing);
- Rabeprazole (Pariet®, Eisai)
Special warnings & precautions (class effect applicable to the above 3 drugs): 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.
New ADR: Hypomagnesaemia. - Pseudoephedrine, triprolidine (Actimin®, CCM Pharmaceuticals) Interactions: Concomitant use of Actimin® with sympathomimetic agents, such as decongestants, tricyclic antidepressants, appetite suppressants and amphetamine-like pyschostimulants or with monoamine oxidase inhibitors which interfere with the catabolism of sympathomimetic amines, may occasionally cause a rise in blood pressure largely because of interaction with pseudoephedrine.
The antibacterial agent, furazolidone, is known to cause a dose-related inhibition of monoamine oxidase. Although there are no reports of hypertensive crises caused by the concurrent administration of Actimin® and furazolidone, they should not be taken together.
Due to its pseudoephedrine content, Actimin® may partially reverse the hypotensive action of drugs which interfere with sympathetic activity including bretylium, bethanidine, guanethidine, debrisoquine, methyldopa and beta adrenergic blocking agents.
Actimin® may, because of its triprolidine content, potentiate the sedative action of other antihistamines, alcohol and other sedatives on the central nervous system.
Lactation: Pseudoephedrine and triprolidine are excreted in breast milk in small amounts but the effect of this on breast-fed infants is not known. It has been estimated that approximately 0.5 to 0.7% of a single dose of pseudoephedrine ingested by a mother will be excreted in the breast milk over 24 hours.
- Ramipril (Tritace®, sanofi-aventis) New ADRs include: Vertigo, ageusia, dysgeusia, impaired psychomotor skills, burning sensation, parosmia, blurred vision, aggravated asthma, fatal pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors); aphtous stomatitis, small bowel angioedema, angioedema with fatal outcome (maybe/become life-threatening, rarely severe course can cause fatal obstruction); exfoliative dermatitis, anorexia, hypotension, vascular stenosis, hypoperfusion, increased antinuclear antibody, increased conjugated bilirubin, hepatocellular damage, cholestatic or cytolytic hepatitis, gynaecomastia, disturbance in attention.
- Tamoxifen (Tamoxifen®, Dynamed) Special warnings & precautions: In the literature it has been shown that CYP2D6 poor metabolisers have a lowered plasma level of endoxifen, one of the most important active metabolites of tamoxifen.
Concomitant medications that inhibit CYP2D6 may lead to reduced concentrations of the active metabolite endoxifen. Therefore, potent inhibitors of CYP2D6 (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should wherever possible be avoided during tamoxifen treatment.
Interactions: Pharmacokinetic interaction with CYP2D6 inhibitors, showing a 65-75% reduction in plasma levels of one of the more active forms of the drug, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants (e.g. paroxetine) in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, cinacalcet or bupropion) should whenever possible be avoided. - Testosterone (Andriol®, Schering-Plough) Special warnings & precautions: Andriol® Testocaps® contains Sunset Yellow (E110, FD&C Yellow no. 6) which may cause allergic reactions.
- Topiramate (Topamax®, J & J) Pregnancy: Topamax® can cause foetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of congenital malformations (e.g. craniofacial defects, such as cleft lip/palate, hypospadias, and anomalies involving various body systems).
Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry indicate an increased risk of oral clefts in infants exposed to topiramate monotherapy during the first trimester of pregnancy. The prevalence of oral clefts was 1.2% compared to a prevalence of 0.39% -0.46% in infants exposed to other AEDs, and a prevalence of 0.12% in infants of mothers without epilepsy or treatment with other AEDs. For comparison, the Centers for Disease Control and Prevention (CDC) reviewed available data on oral clefts in the United States and found a similar background rate of 0.17%. The relative risk of oral clefts in topiramate-exposed pregnancies in the NAAED Pregnancy Registry was 9.6 (95% Confidence Interval = CI 3.6 – 25.7) as compared to the risk in a background population of untreated women. The UK Epilepsy and Pregnancy Register reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed to topiramate monotherapy. The observed rate of oral clefts was 16 times higher than the background rate in the UK, which is approximately 0.2%.
Data from registries and studies indicate that, compared with monotherapy, there is an increased risk of teratogenic effects associated with the use of anti-epileptic drugs in combination therapy.
In treating and counseling women of childbearing potential, the prescribing physician should weigh the benefits of therapy against the risks and consider alternative therapeutic options.
Special populations: Patients with moderate and severe renal impairment may require a dose reduction. Half of the usual starting and maintenance dose is recommended.
Topiramate should be administered with caution in patients with hepatic impairment. - Zoledronic acid (Aclasta®, Novartis) Special warnings & precautions: Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
Atypical femur fractures most commonly occur with minimal or no impact to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.
Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out a femur fracture. Subjects presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.
The optimal duration of use of bisphosphates for the treatment of osteoporosis has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.
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