Bromhexine: Safety in Special Population

Availability

• Tab Bromhexine HCl 8mg
• Syrup Bromhexine HCl 4mg/5ml

Pharmacokinetic

• Metabolism: Extensive hepatic first-pass metabolism
• Excretion: Via urine (approx 85-90%, mainly as metabolites)

Liver Impairment

• There is no pharmacokinetic data available in the elderly or in patients with renal or liver insufficiency.
• Extensive clinical experience did not give rise to relevant safety concerns in these populations.
• However, reduced clearance of bromhexine parent substance may be expected in the case of severe liver disease
• A transient rise in serum aminotransferase values was seen

Renal Impairment

• In the case of severe renal insufficiency, accumulation of metabolites cannot be ruled out

Pregnancy

• Category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
• Bromhexine crosses the placental barrier. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
• Clinical experience to date has shown no evidence of harmful effects on the fetus during pregnancy. Nonetheless, the usual precautions regarding the use of drugs during pregnancy should be observed. Especially during the first trimester, the use of BISOLVON is not recommended.

Lactation

• Bromhexine is excreted in breast milk. Although unfavourable effects on breastfed infants would not be expected, BISOLVON CHESTY is not recommended for use in breastfeeding mothers.

References:

1. Bisolvan Product Information Leaflet
2. MIMS
3. NPRA- Package Insert Template

Conversion: Bisoprolol and Carvedilol

Availability

• Tab Bisoprolol Fumarate 2.5mg & 5mg
• Tab Carvedilol 6.25mg & 25mg

 Dose Equivalence

• Bisoprolol 5mg = Carvedilol 25mg

 General

• There is little or no difference between carvedilol and bisoprolol or metoprolol in hospitalization risk. The certainty of the evidence is high.
• Patients with HF with reduced ejection fraction,  with no or minimal current evidence of fluid retention should be treated with one of the following three beta blockers: carvedilol, extended release metoprolol succinate, or bisoprolol
• All 3 agent improved overall and event-free survival in patients with NYHA class II to III HF and probably in class IV HF

 Carvedilol to Bisoprolol

• Based on recommended initial starting and target doses of these 2 beta-blockers in the various clinical trials CIBIS II, US Carvedilol Studies, and COPERNICUS, and the Clinical Pharmacy Practice Guidelines for HF patients developed by Singapore Ministry of Health,  we decided on a 5:1 dose conversion (eg, carvedilol 12.5 mg BD to bisoprolol 5 mg OM)
• once-daily dosing for bisoprolol compared with a twice-daily dosing of carvedilol is likely to confer a higher likelihood of adherence
• alpha-blockade effect is more likely to cause hypotension and/or dizziness, further discouraging adherence to carvedilol
• Recommendation: Switching from carvedilol to bisoprolol may help with continuation of β-blocker treatment as well as dosage increase in HF patients with adverse symptoms or signs, allowing them to reach the target dose

 References:

1. http://www.ajpb.com/journals/ajpb/2012/ajpb_mayjun2012/therapeutic-interchange-of-carvedilol-to-bisoprolol-for-chronic-heart-failure-the-singapore-experience
2. http://www.sciencedirect.com/science/article/pii/S0914508713000579

 Rationale for Carvedilol

• Reduces mortality in NYHA stage 2-4 has the strongest evidence for benefit in severe failure.
• Greater reduction in mortality than with immediate-release metoprolol tartrate in COMET
• Carvedilol might decrease mortality compared to metoprolol or bisoprolol in patients with heart failure. [The certainty of the evidence is low]
• Using carvedilol is not more expensive than the alternative beta-blockers analysed in this summary. It might have a favorable cost/benefit ratio, but again, it is important to highlight this is based on low certainty evidence

 References:

1. http://www.globalrph.com/beta_blockers.htm
2. http://pharmacistsletter.therapeuticresearch.com/pl/ArticleDD.aspx?nidchk=1&cs=&s=pl&pt=3&fpt=130&dd=290104&pb=&&dddt=3&mobile=2
3. http://www.medwave.cl/link.cgi/English/Updates/Epistemonikos/6169?ver=sindiseno

Corticosteroid in Autoimmune Hemolytic Anemia

• Corticosteroid in autoimmune hemolytic anemia can stop an immune system from, or limit its ability to, make antibodies (proteins) against red blood cells.
• There is a few available regimens recommended for corticosteroid dosing administration.

Journal of the European Hematology Association :

  Prednisolone

•  Initial dose of 1.0–1.5 mg/kg/day for 1–3 weeks until hemoglobin levels greater than 10 g/dL are reached
•  If none or minimal improvement is observed in the third week, this therapy is assumed to be ineffective
•  After stabilization of hemoglobin, prednisone should be gradually and slowly tapered off at 10–15 mg weekly to a daily dose of 20–30 mg, then by 5 mg every 1–2 weeks until a dose of 15 mg, and subsequently by 2.5 mg every two weeks with the aim of withdrawing the drug

Methylprednisolone

• Intravenous methylprednisolone at 100–200 mg/day for 10–14 days or 250–1000 mg/day for 1–3 days

Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria:

Prednisolone

• Initial  dose of 1 mg/kg/d prednisolone is administered until a hematocrit of greater than 30% or a hemoglobin level greater than 10 g/dL (thus, not necessarily a complete normalization of hemoglobin is reached)
•  If this goal is not achieved within 3 weeks, second-line treatment is started because further improvement with steroid treatment is unlikely
• Once the treatment goal is achieved, the dose of prednisolone is reduced to 20 to 30 mg/d within a few weeks
• Thereafter, the prednisolone dose is tapered slowly (by 2.5-5 mg/d per month)
•  An alternate-day regimen by reducing the dose gradually to nil on alternate days may reduce the side effects of steroids

Netherlands the Journal of Medicine:

Prednisolone

• 1 mg/kg/day is started, and depending on the clinical response is tapered slowly
•  After stabilisation of the haemoglobin a scheme frequently used at our department is to taper prednisolone to a dosage to 20 mg/day in two weeks
• If the haemoglobin level remains stable, dosage can further be reduced to 10 mg/day after a month
• Thereafter, the steroid dosage can further be tapered and be stopped after two weeks

Uptodate:

Prednisolone

• The recommended initial doses are quite high - 1 to 1.5 mg/kg per day of prednisolone 
• Doses in children are generally similar
• A successful treatment manifest by a rising hemoglobin concentration, is usually seen within one to three weeks
• Once remission has been achieved, the steroid dose must be tapered.
• In children, this can be done quite rapidly since the disease process is often self-limited. In adults, tapering should be more gradual in an attempt to find the lowest dose that will maintain an adequate remission
• The following tapering down schedule is found to be useful:

References

1. Netherlands the Journal of Medicine. ‘Autoimmune haemolytic anaemia – A practical guide to cope with a diagnostic and therapeutic challenge. Retrieved from http://www.njmonline.nl/getpdf.php?id=1045
2. Official Journal of the European Hematology Association. ‘Treatment of autoimmune hemolytic anemias’.Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181250/
3. Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.’ How I treat autoimmune hemolytic anemias in adults’. Retrieved from http://www.bloodjournal.org/content/bloodjournal/116/11/1831.full.pdf?sso-checked=true
4. Uptodate. 'Warm autoimmune hemolytic anemia: Treatment'. Retrieved from https://www.uptodate.com.ezp.imu.edu.my/contents/warm-autoimmune-hemolytic-anemia-treatment 

IM Dicofenac : can it be given as IV?

Availability

• Injection Diclofenac Injection 75mg/3ml (Dicloran)

Route of administration

• Based on product information, mode of administration specified is Intramuscular
• No information on administration via other routes

Administration via Intravenous Route

• There are several products available that can be given as IV
• However these products are specifically made for such routes / should not be interchanged
• Complications of wrong administration
• Not much information on effect and management of IM injection administered as IV
• Based on several case reports of administration intravenously into arterial route, symptoms seen are gangrene and burning sensations.
• Vasospasm, intravascular thrombosis, chemical endoarteritis are the proposed pathophysiological mechanism
• Intravenous drug administration has been associated with the occurrence of Thrombophlebitis
• Rare adverse events (based on IV diclofenac): cannula site reaction, infusion site discomfort or burning, injection site stinging, or pyrexia

Contraindications for IV Route

• Concomitant NSAID or anticoagulant use (including low dose heparin).
• History of haemorrhagic diathesis, a history of confirmed or suspected cerebrovascular bleeding.
• Operations associated with a high risk of haemorrhage.
• A history of asthma.
• Moderate or severe renal impairment (serum creatinine >160μmol/l).
• Hypovolaemia or dehydration from any cause

References:

1. https://www.ncbi.nlm.nih.gov/pubmed/25738031
2. https://www.medicines.org.uk/emc/medicine/1339
3. http://www.apicareonline.com/letters-to-editor-accidental-intra-arterial-injection-of-diclofenac-sodium-and-their-consequences-report-of-two-cases/

Neomycin vs Gentamicin : Topical

General principle

• Aminoglycosides are effective against aerobic gram negative and some gram positive bacteria. Its mechanism of action is to inhibit protein synthesis by binding with ribosomal RNA, causing      misreading of the bacterial genetic code thus slow down the growth of microorganism.

• The differences in susceptibility/resistance are subtle and related to resistance producing enzymes.

• All aminoglycosides can cause nephrotoxicity, ototoxicity and vestibular toxicity. They also share toxicities like skeletal muscle paralysis and cardiac muscle weakness

Gentamicin

• A product of a strain of Micromonospora purpurea.

• Based on The Gulf Journal of Dermatology and Venereology , it has a similar “spectrum” to related antibiotics such as neomycin, but a rather greater activity than these against some species of bacteria

• Almost all enterobacteria are sensitive to it, including species of Aerobacter, Escherichia, Klebsiella, Salmonella, Shigella, Proteus, and Pseudomonas

•  Advantage : A high degree of activity against Pseudomonas aeruginosa

• Most sensitive gram positive organism:  Staphylococci

• It is bactericidal in concentrations little greater than those inhibiting growth

Neomycin

• Neomycin sulfate is the sulfate salt of neomycin B and C
• Produced by the growth of Streptomyces fradiae
• With the exception of P. aeruginosa, it is bactericidal against most gram 
• negative bacteria; however, it lacks activity against anaerobes
• It is active against some gram-positive bacteria, including staphylococci, but is not effective against streptococc
• Frequently combined with other topical antimicrobials to improve its coverage against gram-positive bacteria

Topical Antibiotic

Gentamicin

Neomycin

Indication

- Treatment of burns      - Bedsore      - Impetigo      - Folliculitis      - Nasal carriers of staphylococci      - Any other localized infection

-  Adjunctive treatment of    burns       - Superficial infection      - Prophylaxis against infection  in minor wounds and postoperative wound      - Superinfection in chronic  dermatoses

Sensitive organism

Gram Negative (-) - Almost all enterobacteria –  (Aerobacter, Escherichia,      Klebsiella,Salmonella,    Shigella, Proteus and Pseudomonas) - A high degree of activity against Pseudomonas Aeruginosa Gram positive (+) - Most sensitive: Staphylococci - Moderate sensitive: Streptococci    (except S. faecalis) & Pneumococci

Gram negative (-) - Bactericidal against most    gram negative bacteria - Lack of activity against    anaerobes. Gram positive (+)      - Active against some gram- positive bacteria, including Staphylococci       - Not effective against Streptococci

Formulation

Gentamicin 0.1% cream             Gentamicin 0.1%ointment

Neomycin0.5% Cream       Neomycin 0.5% Ointment

Availability in Hospital Keningau

Unavailable (alternatively can use     Gentamicin 0.3% eye ointment)

Neomycin 0.5% Cream

Dosage/Application

Adult & child > 1 year : Apply to affected skin 2 times daily

Apply sparingly to affected area up to 2 times daily (for short term us, 1-2 weeks)

Others

Side effect: Redness, itchiness, swelling Special precaution: Avoid prolonged use

Side effect: Skin sensitization or contact dermatitis. The sensitivity disappears once treatment is discontinued Special precaution: Super infection can may occur on prolonged use

Conclusion

• In fact, gentamicin and neomycin are aminoglycosides that demonstrate the same mechanism of action in inhibiting protein synthesis by binding with ribosomal RNA thus slowing the bacteria growth

• The advantage of gentamicin over neomycin is, its broad spectrum activity and the ability to cover Pseudomonas Aeruginosa-caused infection while neomycin is unable to cover it 

• Nevertheless, both neomycin and gentamicin still have the same bactericidal mechanism even to different organisms and due to that similar characteristic, they can be used interchangeably to treat skin infections

References
1.  https://medlineplus.gov/druginfo/meds/a682274.html
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018441/
3. https://www.oregon.gov/oha/healthplan/EvidenceBasedReports/ps-2010-03-antibiotics-topical.pdf
4. Dermatologic Therapy, Vol. 25, 2012, 6–11. Update on Topical Antibiotics in Dermatology. http://apollohealing.com/wp-content/uploads/2015/07/Topical-Antibiotics-in-Dermatology-.pdf
5. Dermatology Pocket Guide: Application of Topical Product, Jabatan Farmasi Hospital Bukit Mertajam, First Edition 2016.
6. The Gulf Journal of Dermatology and Venereology, Volume 17, No.1, April 2010. Topical antibiotics in dermatology: An update http://apollohealing.com/wp-content/uploads/2015/07/Topical-Antibiotics-in-Dermatology-.pdf

Dose Equivalence : ACEi and ARB

Reference:
London New Drugs Group APC/DTC Briefing Document, August 2008.