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

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/

Albendazole & Mebendazole : Pregnancy

Albendazole

• Pregnancy category: C
• Albendazole has been shown to have teratogenic and embryotoxic potential in rats and rabbits.
• It should not be used during pregnancy, if at all possible.
• Manufacturer recommends a pregnancy test prior to therapy in women of reproductive potential.
• Women should be advised to avoid pregnancy during and for at least 1 month following therapy.
• Discontinue treatment if pregnancy occurs during treatment.

 Mebendazole

• Pregnancy category: C
• The available evidences showed no difference in congenital anomalies in the children of women treated with mebendazole during mass treatment programs compared with those who were not.
• In mass treatment programs for which the World Health Organization (WHO) has determined that the benefit of treatment outweighs the risk, WHO allows use of mebendazole in the 2nd and 3rd trimesters of pregnancy.
• CDC suggests postponing therapy until third trimester when possible.

Note

Pregnancy Category C: Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal, or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

References:

1. Centers for Disease Control and Prevention https://www.cdc.gov/parasites/pinworm/health_professionals/ 
2. WHO: Drugs Used in Parasitic Disease
3. http://apps.who.int/medicinedocs/en/d/Jh2922e/3.2.1.html
4. Lexicomp Drug Information Handbook

Metronidazole: Trichomoniasis in Pregnancy

• Treatment reduces symptoms and signs of T. vaginalis infection and might reduce transmission. Likelihood of adverse outcomes in women with HIV also is reduced with T. vaginalis therapy

Recommended Regimen

• Metronidazole 2 g orally in a single dose
  OR
• Tinidazole 2 g orally in a single dose

Alternative Regimen 

• Metronidazole 500 mg orally twice a day for 7 days

• The nitroimidazoles are the only class of antimicrobial medications known to be effective against T. vaginalis infections.
• Of these drugs, metronidazole and tinidazole have been cleared by FDA for the oral or parenteral treatment of trichomoniasis

Rationale in Pregnancy

• Pregnancy Category : B. Use of metronidazole for trichomoniasis is contraindicated during the first trimester; the manufacturer makes no further recommendations regarding use during pregnancy
• T. vaginalis infection in pregnant women is associated with adverse pregnancy outcomes, particularly premature rupture of membranes, preterm delivery, and delivery of a low birthweight infant
• Although metronidazole treatment produces parasitologic cure, certain trials have shown no significant difference in perinatal morbidity following metronidazole treatment.
• One trial suggested the possibility of increased preterm delivery in women with T. vaginalis infection who received metronidazole treatment, yet study limitations prevented definitive conclusions regarding the risks of treatment.
• More recent, larger studies have shown no positive or negative association between metronidazole use during pregnancy and adverse outcomes of pregnancy
• If treatment is considered, the recommended regimen in pregnant women is metronidazole 2 g orally in a single dose.
• Symptomatic pregnant women, regardless of pregnancy stage, should be tested and considered for treatment.
• Treatment of T. vaginalis infection can relieve symptoms of vaginal discharge in pregnant women and reduce sexual transmission to partners.
• Although perinatal transmission of trichomoniasis is uncommon, treatment also might prevent respiratory or genital infection of the newborn
• Although metronidazole crosses the placenta, data suggest that it poses a low risk to pregnant women
• No evidence of teratogenicity or mutagenic effects in infants has been found in multiple cross-sectional and cohort studies of pregnant women
• Women can be treated with 2 g metronidazole in a single dose at any stage of pregnancy.

Reference:

1. https://www.cdc.gov/std/tg2015/trichomoniasis.htm
2. https://www.drugs.com/pregnancy/metronidazole.html

Liver Disease : Safety of Antibiotics

Adapted from Amrapurkar DN. Prescribing medications in patients with decompensated liver cirrhosis. Intl J Hepatology 2011;doi:10.4061/2011/519526: pp 1-5.

Analgesia : In Hepatic Failure

• A pharmacological approach to analgesia in patients with cirrhosis who have no renal failure, active alcoholism, or active substance abuse. 
• Starting doses are used unless otherwise indicated. 
• Doses should be carefully titrated as tolerated
• Avoid polypharmacy and monitor for adverse drug events.

Paracetamol

• In general, for long-term use in cirrhotic patients it is recommended to reduce dosing at 2 to 3 g/d. 
• Although such patients may eliminate paracetamol more slowly than patients without liver disease, repeated administration of the drug does not result in accumulation of hepatotoxic intermediate, NAPQI. 
• Furthermore, there is no evidence of increased CYP enzymes activity or reduced hepatocellular glutathione stores in patients with liver disease.

NSAIDs

• should be avoided in those with both compensated and decompensated cirrhosis, primarily because of the risk of acute renal failure due to prostaglandin inhibition.
• An increased risk of GI mucosal bleeding, variceal hemorrhage, impaired renal function, and development of diuretic-resistant ascites is seen with use of NSAIDs in patients with cirrhosis with portal hypertension
• Selective COX-2 inhibitors
• inadequate data to establish the safety of selective COX-2 inhibitors in patients with advanced CLD or cirrhosis
• If used, celecoxib product information suggests a 50% dose reduction for Child-Pugh class B cirrhosis

Opiods

• should be administrated with a longer interval between doses and possibly lower doses, with individual titration to achieve optimal pain relief without significant adverse effects. 
• Careful follow-up is necessary to check for signs of sedation, opioid-induced constipation and early encephalopathy. 
• Immediate discontinuation of the opioids should be considered if any sign of these complications is appeared.

Fentanyl

• Generally a good choice for patients with CLD or cirrhosis when opiate treatment indicated.
• Useful option in patients with renal failure in setting of cirrhosis.
• No dose adjustment needed for single dose.
• With repeated dosing, reduce dose and frequency by approximately 25 to 50%.
• Initiate transdermal patch at half usual dose. 

Morphine

• Accumulation of metabolites with complex effects (eg, respiratory depression, analgesic tolerance, neurotoxicity) can occur in patients with cirrhosis and renal failure
• Reduce dose and frequency by approximately 50% in advanced CLD or cirrhosis.
• Titrate dose gradually to avoid accumulation of active drug.
• Avoid in patients with cirrhosis and renal failure.

 Tramadol

• Unpredictable onset, variable analgesic efficacy, and risk of accumulation in patients with cirrhosis
• Avoid use in patients with decompensated cirrhosis.
• Avoid use in patients at risk for seizures.
• Based upon limited experience, a reduced dose of 25 mg every eight hours may be considered for treatment of pain in patients with advanced CLD or well-compensated cirrhosis.

References

1.  www.uptodate.com
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861975/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250965/

Aspirin in Pregnancy

• Indication: Preeclampsia
• Dose: 75mg/day

Product Leaflet :

• Aspirin should not be used in pregnancy as it may be associated with prolongation of labour and with maternal and neonatal bleeding.

Lexicomp :

• Salicylates do cross placenta.
• Use of aspirin close to delivery may cause premature closure of the ductus arteriosus.
• Low dose may be used to prevent preeclampsia in women with history of early-onset preeclampsia and preterm delivery, or preeclampsia in more than 1 prior pregnancy.
• Low dose aspirin is used to treat complications resulting from antiphospholipid syndrome in pregnancy (either primary or secondary to SLE)
• Low dose aspirin to prevent thrombosis may also be used during the second and third trimesters in women with prosthetic valves (mechanical or bio prosthetic).
• The use of warfarin is recommended, along with low dose aspirin, in those with mechanical valves.

• In general, low doses during pregnancy needed for the treatment of certain medical conditions have not been shown to cause fetal harm: however, discontinuing therapy prior to delivery is recommended.

Drugs.com:

• Aspirin has not been formally assigned to pregnancy category by the FDA. However, aspirin is considered to be in pregnancy category D by the FDA if full dose aspirin is taken in the third trimester.
• High doses have been associated with increased perinatal mortality, intrauterine growth retardation, and teratogenic effects.
• FDA issued a warning that it is especially important not to use aspirin during the last trimester of pregnancy unless specifically directed to do so by a physician because it may cause problems in the unborn child or complications during delivery.
• Increased maternal bleeding can occur during delivery when aspirin is used 1 week prior to and/or during labor and delivery. Prolonged gestation and labor have been reported due to aspirin's inhibition of prostaglandin.
• Low dose aspirin in pregnancy is safe with respect to the risks of malformation and of major impairment in development at 18 months of age

US Preventive Services:

• Pregnant Women Who Are At High Risk for Preeclampsia: The USPSTF recommends the use of low-dose aspirin (81 mg/d) as preventive medication after 12 weeks of gestation in women who are at high risk for preeclampsia.

WHO Guidelines

Antiplatelets for Prevention of Pre-eclampsia:

• Low-dose acetylsalicylic acid (aspirin, 75 mg/day) is recommended for the prevention of pre-eclampsia in women at high risk of developing the condition. (Moderate-quality evidence, Strong recommendation)
• Low-dose acetylsalicylic acid (aspirin, 75 mg/day) for the prevention of pre-eclampsia and its related complications should be initiated before 20 weeks of pregnancy. (Low-quality evidence, Weak recommendation)