Drug information | Custom PHD Thesis

QUESTION 10
Topic: Adverse effects Written response required: NO

Scenario: A GP calls with an enquiry about one of his patients. The patient has been taking amitriptyline for the 3 weeks and reports having developed tinnitus.

Enquiry: Can tricyclic antidepressants such as amitriptyline cause tinnitus?

Additional questions for enquirer that may help provide a more complete/ detailed response:
How old is the patient
What is the gender: in case of female; does she pregnant or breastfeeding?
Does he has allergy?
When he got tinnitus?
How long he use Amitriptyline? And for what specifically ?
When the patient are using the drug and how many times per day?
What is the dose of Amitriptyline he is on now?
Is there any change in the dose recently?
Does the patient use any Thyroid medication
Does the patient has any cardiovascular disease?
Does the patient has kidney or liver disease?
Does the patient using any other antidepressant?
Does the patient abuse drinking alcohol? How often?
Anticipated additional question(s):
could i have tinnitus from taking Amitriptyline for a short period?

What are the symptom of overdose and when it may start?
Does tinnitus related to TCA toxicity and is it reversible or irreversible?
Do the patients require to do routine blood tests and hepatic functions ? and how often?
Is Amitriptyline safe to use in elderly or children below 2 years?
Does it require tapering the dose and what are the sudden withdrawal effects?
Search strategy/ information obtained from resources:
AMH Nothing found anything relates to tinnitus
Berthold Langguth1,3, Michael Landgrebe1,3, Markus Wittmann1 , Tobias Kleinjung2,3 and Go¨ran Hajak1 Amitriptalyine could cause tinnitus in some patient and it may be a sign of ototoxicity

Drug-induced tinnitus Antidepreessant (e.g: amitryptiline) is associeated with tiniitus

BNF Amitryptaline induced frequent tinnitus

Stockley drug interactionNothing found

Medline plus tinnitus is not consider an overdose of amitryptaline
Medline plus Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
Medline plus Tinnitus is not consider either one of the serious side effectsor an overdose of Amitryptiline, thereore, you can manage it
Response:
Medline plus Tinnitus is not consider either one of the serious side effectsor an overdose of Amitryptiline, thereore, you can manage it
eTGTinnitus usually reflects hair cell damage in the inner ear. Management should be directed at any underlying causes. Unilateral tinnitus or hearing loss should always be investigated to exclude the possibility of an underlying acoustic neuroma.
Management includes reassurance, if there is no serious underlying cause, and awareness of medications that may aggravate tinnitus (eg nonsteroidal anti-inflammatory drugs, antidepressants). Masking techniques may be helpful, including the use of a hearing aid if there is significant hearing loss.
Empirical pharmacological therapy is usually unhelpful. Benzodiazepines have demonstrated limited effectiveness in some studies, but should generally be avoided because of the risk of dependence.
Reference sources used to answer enquiry:

1-BNF Withdrawal effects may occur within 5 days of stopping treatment with antidepressant drugs; they are usually mild and self-limiting, but in some cases may be severe. The risk ofwithdrawal symptoms is increased if the antidepressant is stopped suddenly after regular administration for 8 weeks or more. The dose should preferably be reduced gradually over about 4 weeks, or longer if withdrawal symptoms emerge (6 months in patients who have been on long-term maintenance treatment).
If possible tricyclic and related antidepressants should be withdrawn slowly.
2- eTGTinnitus usually reflects hair cell damage in the inner ear. Management should be directed at any underlying causes. Unilateral tinnitus or hearing loss should always be investigated to exclude the possibility of an underlying acoustic neuroma.
Management includes reassurance, if there is no serious underlying cause, and awareness of medications that may aggravate tinnitus (eg nonsteroidal anti-inflammatory drugs, antidepressants). Masking techniques may be helpful, including the use of a hearing aid if there is significant hearing loss.
Empirical pharmacological therapy is usually unhelpful. Benzodiazepines have demonstrated limited effectiveness in some studies, but should generally be avoided because of the risk of dependence.
3- AMH Nothing found anything relates to tinnitus
4- Berthold Langguth1,3, Michael Landgrebe1,3, Markus Wittmann1 , Tobias Kleinjung2,3 and Go¨ran Hajak1 Amitriptalyine could cause tinnitus in some patient and it may be a sign of ototoxicity
5- Drug-induced tinnitus Antidepreessant (e.g: amitryptiline) is associeated with tiniitus
BNF Amitryptaline induced frequent tinnitus
6- Stockley drug interactionNothing found

7-Medline plus
https://vsearch.nlm.nih.gov/vivisimo/cgi-bin/query-meta?v%3Aproject=medlineplus&v%3Asources=medlineplus-bundle&query=+amitriptyline

• The questions on red colour while the initial answers on black colour
• Initial answer on black colour , you could get some answer from them because i took some of these information from the original text reference then i copy them BUT DONT DEPEND ON them 100% to answer the questions, you should also read the original reference then choose the best answer please
• The references on yellow colour

QUESTION 7
Topic: Medicines Interactions Written response required: NO

Scenario: A call comes through from a community pharmacist. They have a patient with oral thrush and would like to recommend miconazole oral gel. The patient is currently also prescribed rosuvastatin.

Enquiry: Can miconazole oral gel be used in a patient taking rosuvastatin regularly?

Additional questions for enquirer that may help provide a more complete/ detailed response:
If they female, are they pregnant?
How old are the patient? Weight?
Is the patient are using frequent antiobiotic any antibiotic?
Doeas the patient are using any corticosteroid inhaler?
Does the patient has immunocomprimised disease?
Does the patient using Dentures?

What is the cause of oral thrush?
Does the patient has any syndrome that cause the mouth dry?
Does the patient are using antipsychotic or chemotherapy drugs?
Doeas the patient has diabetes or lack of vitamin B12, iron, folic acid
Are you smoker?
Once you prevent the causes it will reduce the subtipility to get oral thrush
Do they have thyroid disorder (e.g: Hypothyrodism)
Do they drink excessive amount of alcohol and how many per week?

Does the patient has any blood disorder, liver and muscle disorders , renal dysfunction ?
Does the patient use or any anticoagulant therapy such as warfarin?
Do they have allergy in general and specifically to Azoles goroup
When do you got oral thrush
What is the dose of rousvastain?

Anticipated additional question(s):
What is the Signs of rhabdomyolysis include muscle pain and weakness and reddish-brown urine (myoglobinuria). 2
liver toxicity; when do we do liver function test and does it to do for the entire duration of the treatment?

Search strategy/ information obtained from resources:
Response:
You should take daktarin oral gel until the symprtoms are clear
MIMIS Dose Drop gel on tongue; keep in mouth for as long as possible before swallowing; treat for greater than or equal to 1 wk after symptoms have cleared. Infants, younger children: divide dose into several portions and place into front of mouth. Adults, children greater than or equal to 2 yrs: 1/2 spoonful using provided measuring spoon 4 times daily; infants 6-24 mths: 1/4 spoonful using provided measuring spoon 4 times daily; elderly with dentures: also apply to dentures overnight, wash off before replacing dentures in morning

eTG identification of underlying predisposing factors and local precipitating factors, such as ill-fitting dentures, and prevented
eTG miconazole 2% gel 2.5 mL (child 6 months to 2 years: 1.25 mL) topically (then swallowed), 4 times daily, after food, for 7 to 14 days (measuring spoon supplied with pack). Place directly in the mouth and on the tongue [Note 2]
Continue treatment for several days after symptoms resolve. Advise denture wearers to apply the antifungal to the cleaned fitting surface of the dentures before inserting them.
Reference sources used to answer enquiry:

References

1-Stockley Raised statin concentrations are known to be associated with the development of myopathy and rhabdomyolysis
2-Australian medicine handbook (AMH)/ Warfarin+miconazolemay increase its anticoagulant effect and risk of bleeding
;Monitor INR and reduce warfarin dose as needed.
AMH/ For most drug interactions it is appropriate to temporarily stop or reduce the dose of the other drug, monitor the clinical and adverse effects and/or measure the drug concentration
AMH/ azoles + simvastatin
Azoles may increase concentration of simvastatin and increase the risk of myopathy or rhabdomyolysis; temporarily stop simvastatin while the azole is being taken or consider using pravastatin (less likely to be affected). Combinations (except with fluconazole) are contraindicated by manufacturer.

AMH/ Drug interactions may rarely occur with miconazole, as some systemic absorption of miconazole occurs from the oral gel, vaginal and topical products.
3- Stockley Drug intercation Miconazole slightly increase rousvastatin exposure
Stockley Drug intercation  Case reports describe rhabdomyolysis associated with the use of an azole group
Stockley Drug intercation  iconazole is an inhibitor of CYP2C9 and would be expected to interact like fluconazole

Stockley Drug intercation  Just how statins cause muscle disorders is as yet unclear, although it is thought to be connected to elevated statin concentrations
Stockley Drug intercation elevated hepatic transaminases are dose dependent, although progression to liver failure is exceedingly rare. 4 Any pharmacokinetic interaction that results in a marked rise in statin concentrations is therefore to be regarded seriously.
Stockley Drug intercation the overall risk of myopathy with the statins at standard therapeutic doses is quite low and commonly quoted as 0.01 to 0.1%, although in clinical studies involving patients taking statins
Stockley Drug intercation  However, it has been estimated that for every 15 million prescriptions there is only one occurrence of severe muscle damage. 7 The incidence seems to rise markedly if other interacting drugs are being taken concurrently.
4- 7- Thompson, PD, Clarkson PM, Rosenson RS; the National Lipid Association’s Muscle Safety Expert Panel. An Assessment of statin safety by muscle experts. Am J Cardiol (2006) 97 (Suppl), 69C–76C.(PubMed)
Stockley Drug intercation  the patien asked to promptly report muscle pain, tenderness, or weakness, especially if this is accompanied by malaise, fever, or dark urine. 9

5- American Jornal cardiologyMyopathy is more likely to occur at higher statin doses than at lower doses
6-the National Lipid Association Safety Assessment Task Force 1 give some important safety recommendations, which are useful in the context of interactions:
Routine monitoring of creatine kinase is of little value in the absence of clinical symptoms.
If a patient has intolerable muscle symptoms or a creatine kinase value 10 times the upper limit of normal, and is symptomatic, statin treatment should be immediately discontinued.
If a patient has symptoms of muscle pain with a creatine kinase of up to 10 times the upper limit of normal they should be monitored closely. The statin may be continued at the same or reduced doses and symptoms and creatine kinase concentrations can be used as the clinical guide to stop or continue treatment.
If progressive creatine kinase elevations occur consider a dose reduction or temporary discontinuation of the statin.
Liver transaminase concentrations should be obtained during routine general evaluation of patients being considered for a statin.
Liver enzyme values of up to 3 times the upper limit of normal do not represent a contraindication to treatment but patients should be carefully monitored.
7-McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol (2006) 97 (Suppl), 89C–94C.(PubMed)
Stockley Drug intercation  (b) Pharmacokinetics
1. Cytochrome P450 isoenzymes
Lovastatin and simvastatin are extensively metabolised by CYP3A4, and drugs that inhibit this isoenzyme can cause marked rises in blood statin concentrations. Atorvastatin is also metabolised by CYP3A4, but to a lesser extent than lovastatin or simvastatin. Some of the statins are not metabolised by this isoenzyme so they interact differently. Fluvastatin is metabolised primarily by CYP2C9 (with a minor contribution from other isoenzymes, including CYP3A4), only 10% of rosuvastatin is metabolised, and the isoenzymes involved appear to be CYP2C9 and CYP2C19,

Stokley rosuvastatin seem to have no effect P-glycoprotein substrates, and inhibitors of this carrier might therefore interact resulting in altered oral bioavailability

8-BNF April 2016 update Fungal infections of the mouth are usually caused by Candida spp. (candidiasis or candidosis). Different types of oropharyngeal candidiasis are managed as follows:
Thrush
Acute pseudomembranous candidiasis (thrush), is usually an acute infection but it may persist for months in patients receiving inhaled corticosteroids, cytotoxics or broad-spectrum antibacterials. Thrush also occurs in patients with serious systemic disease associated with reduced immunity such as leukaemia, other malignancies, and HIV infection. Any predisposing condition should be managed appropriately. When thrush is associated with corticosteroid inhalers, rinsing the mouth with water (or cleaning a child’s teeth) immediately after using the inhaler may avoid the problem. Treatment with nystatin or miconazole may be needed.Fluconazole is effective for unresponsive infections or if a topical antifungal drug cannot be used or if the patient has dry mouth. Topical therapy may not be adequate in immunocompromised patients and an oral triazole antifungal is preferred.

Electronic therapeutic guideline (eTG) identification of underlying predisposing factors and local precipitating factors, such as ill-fitting dentures, and prevented
Electronic therapeutic guideline (eTG) miconazole 2% gel 2.5 mL (child 6 months to 2 years: 1.25 mL) topically (then swallowed), 4 times daily, after food, for 7 to 14 days (measuring spoon supplied with pack). Place directly in the mouth and on the tongue [Note 2]
Continue treatment for several days after symptoms resolve. Advise denture wearers to apply the antifungal to the cleaned fitting surface of the dentures before inserting them.
9- MIMS Online
https://www-mimsonline-com-au.dbgw.lis.curtin.edu.au/Search/AbbrPI.aspx?ModuleName=Product%20Info&searchKeyword=Miconazole&PreviousPage=~/Search/QuickSearch.aspx&SearchType=&ID=9110001_2

MIMS Online says miconazole is contraindicated in HMG-CoA reductase inhibitors (eg simvastatin, lovastatin) but not with Rousvastain

Dose Drop gel on tongue; keep in mouth for as long as possible before swallowing; treat for greater than or equal to 1 wk after symptoms have cleared. Infants, younger children: divide dose into several portions and place into front of mouth. Adults, children greater than or equal to 2 yrs: 1/2 spoonful using provided measuring spoon 4 times daily; infants 6-24 mths: 1/4 spoonful using provided measuring spoon 4 times daily; elderly with dentures: also apply to dentures overnight, wash off before replacing dentures in morning
QUESTION 20
Topic: Medicines in Pregnancy Written response required: NO

Scenario: A member of the public calls the DI department. She wants to know if fexofenadine is safe to use during pregnancy for the management of hay fever.

Enquiry: Can fexofenadine be used to treat hay fever during pregnancy?

Additional questions for enquirer that may help provide a more complete/ detailed response:
In which trimester is she in?
What is the classification of hay fever; mild, severe or chronic?
Does she have swallowing problems or she prefer oral liquids?
Does she has allergy?
Does she has pets ?
Does she has eczema or ashma?
Does she use any other medicines (e.g: Aspirin, NSAIDs, anticholinergic drugs..etc) , corticosteriods or any other dosage form of an antihistamine, and immunotherapy?
Does the patient has renal
Does she has any other diseases or kidney diseases?
Where she live; industrial area or dusty area; since birth or recently?
When the hey fever is developed?
Does she has flowers plants containing pollen at home
Are the symptoms intermittent or persistent?
Does she smoke?
Do you have an infection?
is the hay fever chronic?

Anticipated additional question(s):
Does the hay fever require any Skin or blood testing for specific IgE levels to know the severity?’
Can the patient recover withing a short period of time after continuing the drug or it would stay forever?
Is a female more susceptible to get nonallergic rhinitis during pregnancy?
Search strategy/ information obtained from resources:
eTG Skin or blood testing for specific IgE levels is required if making recommendations regarding allergen avoidance
Classification of allergic rhinitis by symptom duration and severity (Table 9.19)
Duration of symptoms
Intermittent Persistent
symptoms present:
on less than 4 days a week
OR
for less than 4 consecutive weeks symptoms present:
on more than 4 days a week
AND
for more than 4 consecutive weeks
Severity of symptoms
Mild Moderate to severe
all of the following present:
symptoms present but not troublesome
normal sleep
no impairment of daily activities, leisure and/or sport
no impairment of school or work performance one or more of the following present:
troublesome symptoms
sleep disturbance
impairment of daily activities, leisure and/or sport
impairment of school or work performance

eTG Fexofenadione is classified within a drug that used in pregnancy as Category B2: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.
eTG Drugs can cause rhinitis by different pathological or pharmacological mechanisms. Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), vasodilator drugs (eg some antihypertensives), intranasal decongestants (causing rhinitis medicamentosa) and oral contraceptives can all cause drug-induced rhinitis
AMH Fexofenadione is Pregnancy Safe to use during pregnancy although there is more experience with older sedating antihistamines
AMH In renal patient Consider reducing initial dose if CrCl <30 mL/minute.
AMHCounselling
This medicine may not work as well if you drink grapefruit juice within 4 hours of taking fexofenadine.
Oral liquid: you can take this medicine with or without food, but if you take it with a fatty meal, it may not be absorbed as well.
AMHThis medication makes some people sleepy; don’t drive or operate machinery if this occurs.
AMHsome antihistamines are available with decongestants and/or analgesics for relief of the symptoms of influenza, the common cold and allergies; there is little rationale for these combinations; avoid use
antihistamines are effective in relieving itch that is due to histamine release (eg in urticaria), however, there is limited evidence for their efficacy in itch due to other causes (where sedating antihistamines appear to reduce itch by causing sedation) antihistamines should be stopped approximately 4 days before skin-prick testing

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk No reports describing the use of fexofenadine during human pregnancy have been located. However, studies in rats found dose-related embryo and fetal toxicity, but the risk to a human fetus cannot be assessed at this time. Because of the extensive human data available, several reviews have recommended that oral first-generation antihistamines (e.g., chlorpheniramine or tripelennamine) should be considered if antihistamine therapy during pregnancy (especially in the 1st trimester) is required (1,2 and 3). The second-generation agents, cetirizine or loratadine, were considered acceptable alternatives, except during the 1st trimester, if a first-generation antihistamine was not tolerated.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal RiskFexofenadine is a second-generation (peripherally selective), histamine H1-receptor antagonist that is used for the relief of symptoms associated with seasonal allergic rhinitis (4). It is a metabolite of another second-generation antihistamine, terfenadine (no longer available). As a group, second-generation antihistamines are less sedating than first-generation agents.
Fertility studies in rats and reproduction studies in rats and rabbits have been conducted with fexofenadine. In rats, doses producing systemic exposures that were ≥3 times the human exposure obtained with a 60-mg twice-daily dose (HTD) were associated with a dose-related decrease in the number of implantations and an increase in the number of postimplantation losses. No evidence of teratogenicity was noted in pregnant rats and rabbits at oral doses up to 4 and 47 times the HTD, respectively. However, dose-related decreases in pup weight gain and survival were observed in rats at three times the HTD (4).
It is not known if fexofenadine crosses the human placenta to the fetus. The molecular weight (about 502 for the free base) is low enough that transfer to the fetus should be expected.

Reference(4) 4. Product information. Allegra. Hoechst Marion Roussel, 2000.

Response:

Season may worsen then hay fever
eTG fexofenadione use 120 mg as a single or divided daily dose for….(Duration)?
AMH120 mg daily in 1 or 2 doses or 180 mg once daily.
AMHCrCl <30 mL/minute ; Adult, initially 60 mg once daily.
eTG Fexofenadione is classified within a drug that used in pregnancy as Category B2: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk No reports describing the use of fexofenadine during human pregnancy have been located. However, studies in rats found dose-related embryo and fetal toxicity, but the risk to a human fetus cannot be assessed at this time. Because of the extensive human data available, several reviews have recommended that oral first-generation antihistamines (e.g., chlorpheniramine or tripelennamine) should be considered if antihistamine therapy during pregnancy (especially in the 1st trimester) is required (1,2 and 3). The second-generation agents, cetirizine or loratadine, were considered acceptable alternatives, except during the 1st trimester, if a first-generation antihistamine was not tolerated.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal RiskFexofenadine is a second-generation (peripherally selective), histamine H1-receptor antagonist that is used for the relief of symptoms associated with seasonal allergic rhinitis (4). It is a metabolite of another second-generation antihistamine, terfenadine (no longer available). As a group, second-generation antihistamines are less sedating than first-generation agents.
Fertility studies in rats and reproduction studies in rats and rabbits have been conducted with fexofenadine. In rats, doses producing systemic exposures that were ≥3 times the human exposure obtained with a 60-mg twice-daily dose (HTD) were associated with a dose-related decrease in the number of implantations and an increase in the number of postimplantation losses. No evidence of teratogenicity was noted in pregnant rats and rabbits at oral doses up to 4 and 47 times the HTD, respectively. However, dose-related decreases in pup weight gain and survival were observed in rats at three times the HTD (4).
It is not known if fexofenadine crosses the human placenta to the fetus. The molecular weight (about 502 for the free base) is low enough that transfer to the fetus should be expected.

Reference sources used to answer enquiry:

1. Australian Medicine Handbook (AMH)

2. eTG
http://etg.hcn.com.au.dbgw.lis.curtin.edu.au/desktop/index.htm

3. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk

4. Product information. Allegra. Hoechst Marion Roussel, 2000.

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