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There are increasing reports to the Centre for Adverse Reaction Monitoring (CARM) of rhabdomylitis due to interactions with simvastatin, resulting from serum concentrations of simvastatin increasing over 200 times. Important medicines to be wary of:
Drug interactions can be broadly categorised as pharmacokinetic or pharmacodynamic. In pharmacokinetic interactions there is a change in the plasma concentration of the interacting drug which can lead to toxicity or sub-therapeutic effect. In a pharma-
codynamic interaction there is a modification of pharmacological effect without a change in plasma concentration; for example,
– Serum concentration may increase up to 200-fold
additive anticholinergic effects seen with amitriptyline and oxybutinin or serotonin syndrome which can occur with an SSRI and
tramadol. This resource mainly focuses on major pharmacokinetic drug interactions that may be seen in general practice and
their management. It is not a comprehensive resource.
– Serum concentrations may increase up to 80-fold
table of commonly used medIcInes that Interact
– Limited data for roxithromycin. If used, ensure the patient is very aware to report any
The table has interactions that are relatively common or carry a high risk of toxicity in red
, moderate interactions in blue
minor interactions in green
and interactions to be aware of in black
. The table quantifies the potential interaction by reporting
– Serum concentrations may increase up to 60-fold
what are generally the maximum potential increases in serum concentration. Where the percentage increase is given, e.g. 300%
– A relatively common combination, but many reports to CARM of simvastatin-induced rhabdomylitis have the combination
increase, then this means that the serum concentration may be increased threefold, which is similar to giving three times the
dosage of the target medicine. Hence many of the interactions are dependent on the initial dosage of the target medicine. As an
– Ensure the patient knows to report any muscle aches immediately
example, the interactions with simvastatin have become more significant with the higher dosages of simvastatin being used.
– Check the lipid profile 4–6 weeks after the combination (plus ALT) and consider down titrating the simvastatin if the lipid
Because of the variability in individual metabolism, many interactions will not be obvious in most individuals, but when an inter-
action occurs, it may lead to considerable morbidity, or mortality. The usual way to manage the potential interaction is through
– There are increasing reports that this is a significant interaction for some people.
conscientious monitoring and general awareness of the clinical symptoms of toxicity. If a new medicine has been added and a new symptom occurs, be suspicious of an interaction, not just an adverse effect.
• Erythromycin, clarithromycin and roxithromycin
Questions to ask when about to prescribe a potentially interacting medicine:
– Increasing reports of high INR results, some resulting in hospitalisation
• Is the combination really necessary—what are the alternatives?
– If the combination is really necessary, monitor the INR in 3 days.
• What are the likely adverse effects of high dosages of the target medicine (how hazardous)?• What clinical monitoring does the patient need to know about to report back to you?
• What objective monitoring needs to be done, and when?
– If tramadol is used, it should be used consistently and monitor INR in 3 days, then 1 week if there was no change.
the red alert drugs and InteractIons
The following medicines should ‘ring alarm bells’ as having important interactions:
– Monitor INR weekly for 4 weeks (onset usually seen in 2 weeks).
particularly simvastatin (not pravastatin)
particularly erythromycin, clarithromycin (less with roxithromycin, minimal with azithromycin)
particularly fluoxetine, paroxetine; less so citalopram
– May get 40-fold increase in tricyclic antidepressant
– Warn the patient about symptoms of serotonin syndrome / toxicity.
– The Australian Adverse Drug Reaction Centre has had an increasing number of reports of serotonin toxicity with the
particularly carbamazepine, phenytoin; less so valproate, gabapentin
combination of tramadol and an SSRI, especially if in combination with a tricyclic antidepressants or an antipsychotic medicine.
As well as searching the primary literature, the David Flockhart Interaction website was used for the cytochrome P450 enzyme table (www.drug-interactions.com) and Stockley’s Drug Interactions textbook.
This is the combination of an ACE Inhibitor (or angiotensin II antagonist) plus diuretic (or dehydration) plus NSAID (or
This table was developed for the Goodfellow Unit Symposium (2007) by Drs Linda Bryant (Clinical Advisory Pharmacist, Department of General Practice and Primary Health Care, University of Auckland; East Health PHO; and Comprehensive Pharmaceutical Solutions Ltd) and
COX-2 Inhibitor) and is an important risk factor for renal failure, especially in the older person.
Tana Fishman (Senior Lecturer, Department of General Practice and Primary Health Care, University of Auckland), and further developed with assistance from Robert Buckham (Chief Drug Information Pharmacist, Christchurch Hospital) and David Woods (BPAC).
VOLUME 1 • NUMBER 2 • JUNE 2009 J OURNAL OF PRIMARY HEALTH CARE
Breakthrough bleeding Unlikely interaction.
Although low risk, high Unlikely interaction.
No published reports. No published reports.
No published reports. No published reports.
Least likely macrolide Least likely macrolide
important. Be alert for information. High
Also negative inotropic contraceptive failure.
– may increase tramadol some cases.
concentrations. Monitor Warn about sedation,
interaction. Monitor for interaction.
toxicity, increased seizure an alternative
Care if also on a TCA.
Effect of verapamil can contraceptive dosage.
st Johns Wort
– Diuretics, ACE inhibitor (or Angiotensin II antagonist) plus NSAID (or COX-2 inhibitor).
Avoid or monitor renal function in 7–10 days, then in 1 month.
Warfarin and tramadol
Avoid combination. Monitor INR in 3–5 days. Regular tramadol is preferable to prn.
lithium and ace inhibitors or diuretics or nsaIds
Increased lithium concentrations possible.
Monitor lithium weekly for 2 weeks (NSAID), 6 weeks (ACE Inhibitor), 4 weeks (NSAID).
allopurinol and azathioprine
Increased azathioprine concentrations.
antibiotics and oral contraceptives
This interaction is very unlikely but due to the consequences using extra precautions is suggested (equates to 7-day rule). Probably more risk with broad spectrum.
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