Appendix 7a: Hepatic Impairment

Appendix 7a: Hepatic Impairment

Dosing considerations in hepatic impairment Hepatobiliary system plays an important role in the interac- tions between drugs and the body. Liver diseases can affect

pharmacokinetics and pharmacodynamics of various drugs.

However there has to be moderate to severe hepatic impair-

ment to significantly alter the response to drugs as liver has a

large reserve capacity. Hepatic impairment may alter response

to drugs not only because of its role in metabolism of drugs

but it also affects their absorption and distribution. Looking at

the importance of liver in dealing with the drug, knowledge of

a patient’s hepatic function is required for the safe prescribing

of many drugs. Unlike renal disease, where estimation of

renal function based on creatinine clearance can fairly help in

knowing the drug elimination and, hence, dose adjustment,

there is no endogenous marker for hepatic clearance that can

be used as a guide for drug dosing.

Hepatic impairment can lead to altered response to drugs due

to all or some of the following reasons:

• Metabolism of many drugs depend on adequate liver function. Generally, metabolism result in the loss of pharmacological activity and, therefore, reduced metabolism in case of impaired liver function can lead to the accumulation of drug in the body to the toxic level at the normal dose. However, in some cases drugs are metabolised to the active form and in these drugs normal dose may not be able to achieve desired response.

• For drugs with low bioavailability (high hepatic extrac- tion), bioavailability increases and hepatic clearance decreases in cirrhotic patients. If such drug is to be administered orally to cirrhotic patients, their initial dose has to be reduced according to their hepatic extraction. For drugs with low bioavailability (low hepatic extraction), hepatic clearance may be affected due to impaired metabolism. For such drugs, only the maintenance dose has to be adjusted according to esti- mated decrease in their hepatic metabolism.

• Portal hypertensive gastropathy and ulcers of upper gastrointestinal tract, frequently seen in cirrhotic patients, may alter the absorption of orally adminis- tered drugs. Absorption of drugs may be increased because of high intestinal permeability in patients

with portal hypertension. Impaired gastrointestinal motility seen in cirrhotic patients can lead to delayed drug absorption.

• Volume of distribution of hydrophilic drugs is increased due to presence of oedema and/or ascitis. Hence, loading dose of these drugs may have to be increased if a rapid action is required. On the other hand, increase in volume of distribution is associated with an increase in the elimination half life of such drugs.

• Impaired elimination of drugs, which are excreted in the bile, can lead to their accumulation in the body.

• Impaired albumin production can lead to decreased protein binding and increased toxicity of highly plasma protein bound drugs.

• High percentage of drugs may reach systemic circu- lation without passing through liver due to develop- ment of portosystemic shunts in cirrhotic patients.

• Cirrhotic patients can often have impaired renal func- tion and in these cases dosage of the drugs have to be carefully adjusted.

The use of certain drugs in patients with cirrhosis may increase the risk of hepatic decompensation. In patients with impaired liver function, dose related hepatotoxic reaction may occur at lower doses. Drugs that cause fluid retention (e.g., pred- nisolone, ibuprofen, dexamethasone, etc.) may exacerbate oedema and ascitis in chronic liver disease. Sensitivity of brain to depressant action of some drugs (e.g., morphine and barbiturates) is markedly increased in cirrhotic patients and can precipitate hepatic encephalopathy at normal doses.

As evident from above, there are complex interactions between the drugs and liver function. Absence of any endog- enous marker for hepatic clearance makes it highly difficult to accurately adjust the dose of various drugs in hepatic impairment. Therefore, if no immediate pharmacological effect is needed, drug therapy should be started cautiously in these patients and titrated individually until desired effect is achieved or toxicity appears. Drugs with a narrow therapeutic range and low hepatic extraction (e.g., theophylline) are the most dangerous drugs. If such drugs are administered orally, both loading dose and maintenance doses have to be reduced by ≥ 50% of the normal dose, depending on the severity of hepatic impairment.

The following table contains information to help prescribing common drugs in hepatic impairment. The table provided is

not exhaustive and abscence from this table does not imply safety of drug, it is, therefore, important to refer to the indi- vidual drug entries.

Drug

Status

Comments

Abacavir

Avoid in severe

hepatic impairment

Avoid in moderate hepatic impairment unless essential

Acetylsalicylic acid

Avoid in severe

hepatic impairment

Increased risk of

Gastrointestinal bleeding

Allopurinol

Reduce the dose

Aluminium hydroxide

Avoid in severe

hepatic impairment

Can precipitate hepatic encephalopathy by causing constipation; Antacids containing high amount of sodium to be avoided in patients with fluid retention

Amidotrizoate

Use with caution

Amitryptyline

Avoid in severe

hepatic impairment

Increased sedation

Amlodipine

Reduce dose

Half life of amlodipine is prolonged

Amodiaquine

Avoid in hepatic impairment

Amoxycillin + Clavulanic acid

Use with caution

Monitor liver function, cholestatic jaundice reported either during or shortly after therapy (more common in

males and patients over

65 years), duration of

treatment should not

exceed 2 weeks

Azathioprine

Reduce dose

Azithromycin

Avoid

May cause jaundice

Bupivacaine

Avoid or reduce dose in severe hepatic impairment

Carbamazepine

Avoid in severe moderate to severe hepatic impairment

Cautiously given in mild hepatic impairment

Ceftriaxone

Reduce dose and monitor plasma concentration if there is associated renal impairment

Chlorambucil

Reduce dose and use cautiously in hepatic impairment

Chloramphenicol Avoid if possible; reduce dose and monitor plasma concentration
Increased risk of bone marrow depression
Chlorpheniramine Avoid May cause inappropriate sedation
Chlorpromazine Use with caution May precipitate coma
Clindamycin Reduce dose
Clomifene Avoid in severe
hepatic impairment
Clomipramine Avoid in severe
hepatic impairment
Increased sedation
Cloxacillin Use with caution Cholestatic jaundice may occur up to several weeks after treatment has stopped; risk increases with increasing age and
if given for more than 2 weeks
Codeine Avoid or reduce dose
Contraceptive, oral Avoid in case of active liver disease
May precipitate coma; Causes constipation
Avoid if history of cholestasis and pruritus during pregnancy
Cyclophosphamide Reduce dose Monitor plasma level
Cyclosporine Reduce dose and
use with caution
Cytarabine Reduce dose
Dacarbazine Avoid in severe
Hepatotoxic
Dose reduction in mild
hepatic impairment to moderate hepatic impairment
Daunorubicin Reduce dose Use with caution as toxicity increases in hepatic impairment
Diazepam Avoid in severe
hepatic impairment
Didanosine Monitor for toxicity
Doxorubicin Reduce dose according
to bilirubin concentration
Doxycycline Avoid or use with caution
Can precipitate coma
Efavirenz Avoid in severe
Dose reduction and/or
hepatic impairment use with caution in mild to moderate hepatic impairment
Enalapril Use with caution Closely monitor liver function in patients with hepatic impairment
Ergometrine Avoid in severe
hepatic impairment
Erythromycin Avoid in severe
May cause idiosyncratic
hepatic impairment hepatotoxicity
Ethinylestradiol Avoid See also Contraceptives, Oral
Etoposide Avoid in severe
Increased risk of toxicity
hepatic impairment in case of hepatic impairment
Fluconazole Use with caution Hepatotoxicity
5-Fluorouracil Use with caution; dose reduction may be required
Fluoxetine Reduce dose or administer on alternate days
Fluphenazine Avoid in severe
Hepatotoxic, can
hepatic impairment precipitate coma
Furosemide Avoid or use with caution in severe hepatic impairment
Glibenclamide Avoid or reduce the dose
Griseofulvin Avoid in severe
hepatic impairment
Hypokalaemia may precipitate coma (use potassium sparing diuretic to prevent this); Increased risk of hypomagnesaemia in alcoholic cirrhosis
Increased risk of hypoglycaemia; can produce jaundice
Haloperidol Use with caution Can precipitate coma
Heparin Reduce dose in
severe liver disease
Hydralazine Reduce dose
Hydrochlorothiazide Avoid in severe
Hypokalaemia may
hepatic impairment precipitate coma (use potassium sparing diuretic to prevent this); increased risk of hypomagnesaemia in alcoholic cirrhosis
Ibuprofen Avoid in severe
Increased risk of
hepatic impairment gastrointestinal bleeding and can also cause fluid retention
Indinavir Reduce dose to 600 mg 8th hly in mild to
moderate hepatic impairment; not studied in severe hepatic impairment
Isoniazid Use with caution Regularly monitor liver function and particularly frequently in first 2 months
Levonorgestrel Use with caution in active liver disease and recurrent cholestatic
jaundice
Lidocaine Avoid or reduce the dose in severe hepatic impairment
Magnesium hydroxide/sulphate
Medroxyproges-
Avoid in hepatic coma if risk of renal failure
Avoid in active liver Avoid if history of pruritus
terone
disease
and cholestasis during pregnancy
Mefloquine Avoid for prophylaxis in severe liver disease
6-Mercaptopurine May need dose reduction
Metformin Avoid Withdraw if tissue hypoxia likely
Methadone Avoid or reduce the dose
Methotrexate Avoid in severe
May precipitate coma
Hepatotoxic; monitor
hepatic impairment liver functions
Methyldopa Avoid in active liver
disease
Metoclopramide Reduce dose
Metronidazole Reduce total daily dose to one third and give once daily in case of severe hepatic impairment
Morphine Avoid or reduce the dose
Nevirapine Avoid in severe
May precipitate coma
Use with caution in
hepatic impairment moderate hepatic impairment
Nitrofurantoin Use with caution Cholestatic jaundice and chronic active hepatitis reported
Norethisterone Avoid in active liver Avoid if history of pruritus
disease.
Ofloxacin Reduce dose in severe hepatic impairment
Paracetamol Avoid large doses- dose related toxicity
Phenobarbital Avoid in severe
hepatic impairment
Phenytoin Reduce dose to
avoid toxicity
and cholestasis during pregnancy
Hepatic dysfunction
reported
May precipitate coma
Prednisolone Use with caution Adverse effects more common
Procainamide Avoid or reduce the dose
Procarbazine Avoid in severe
hepatic impairment
Promethazine Avoid in severe
May precipitate coma;
hepatic impairment Hepatotoxic
Propylthiouracil Reduce dose
Pyrazinamide Avoid in severe
Monitor hepatic
hepatic impairment function- idiosyncratic hepatotoxicity more common
Pyrimethamine Use with caution
Ranitidine Reduce dose Increased risk of confusion
Ribavirin Avoid in severe
hepatic impairment
Rifampicin Avoid or do not exceed 8 mg/kg daily
Monitor liver function
Saquinavir Avoid in
severe hepatic
impairment;
Caution in
moderate hepatic
impairment
Simvastatin Avoid in active liver disease
or unexplained persistent elevation in serum transaminases
Sodium
nitroprusside
Avoid in severe
hepatic impairment
Sulfadiazine Avoid in severe
hepatic impairment
Sulfamethoxazole +
trimethoprim
Avoid in severe
hepatic impairment
Suxamethonium Prolonged apnoea may occur in severe liver disease due to reduced hepatic synthesis of plasma cholinesterase
Testosterone Preferably avoid Possibility of dose related toxicity and fluid retention
Thiopental Reduce dose in
severe liver disease
Valproic acid Avoid, if possible Hepatotoxicity and hepatic failure may occasionally occur (usually in first 6 months)
Verapamil Reduce oral dose
Vinblastine Reduction of dose may require
Vincristine Reduction of dose may require
Warfarin Avoid in severe
liver disease
Zudovudine Reduction of dose as accumulation may occur
Reduced production of clotting factors in hepatic impairment; may increase risk of bleeding

Appendix 7b: Lactation

Administration of some drugs (e.g., ergotamine) to nursing mothers may harm the infant, whereas administration of others (e.g., digoxin) has little effect. Some drugs inhibit lacta- tion (e.g., estrogens).

Toxicity to the infant can occur if the drug enters the milk in pharmacologically significant quantities. The concentration in milk of some drugs (e.g., iodides) may exceed that in the maternal plasma so that therapeutic doses in the mother may cause toxicity to the infant. Some drugs inhibit the infant’s sucking reflex (e.g., phenobarbital). Drugs in breast milk may, at least theoretically, cause hypersensitivity in the infant even when the concentration is too low for a pharmacological effect.

The following table lists drugs:

• which should be used with caution or which are contrain- dicated in lactation for the reasons given above;

• which are not known to be harmful to the infant although they are present in milk in significant amounts.

For many drugs; insufficient evidence is available to provide guidance and it is advisable to administer only drugs essen- tial to a mother during lactation. Because of the inadequacy of information on drugs in breast milk, the following table should be used only as a guide; absence from the table does not imply safety.

n
Benzathine benzylpenicillin
Trace amounts in milk; safe in usual dosage; monitor infant
Benzylpenicillin Trace amounts in milk; safe in usual dosage; monitor infant
Betamethasone Systemic effects in infant unlikely with maternal dose of less than equivalent of prednisolone 40 mg daily; monitor infant’s adrenal function with higher doses
Bleomycin Lactation contraindicated
Carbamazepine Continue lactation; adverse effects possible (severe skin reaction reported in
1 infant); monitor infant for drowsiness;
Ceftazidime Excreted in low concentrations; safe in usual dosage; monitor infant
Ceftriaxone Excreted in low concentrations; safe in usual dosage; monitor infant
Chlorambucil Lactation contraindicated
Chloramphenicol Continue lactation; use alternative drug if possible; may cause bone-marrow toxicity in infant; concentration in
milk usually insufficient to cause ‘grey syndrome’
Chlormethine Lactation contraindicated
Chloroquine For malaria prophylaxis, amount probably too small to be harmful; inadequate for reliable protection against malaria, ; avoid lactation when used for rheumatic disease
Chlorpheniramine Safe in usual dosage; monitor infant for drowsiness
Chlorpromazine Continue lactation; adverse effects possible; monitor infant for drowsiness
Ciprofloxacin Continue lactation; use alternative drug if possible; high concentrations in breast milk
Cisplatin Lactation contraindicated
Clindamycin Amount probably too small to be harmful but bloody diarrhoea reported in 1 infant
Clomifene May inhibit lactation
Clomipramine Small amount present in milk; continue lactation; adverse effects possible; monitor infant for drowsiness
Clonazepam Continue lactation; adverse effects possible; monitor infant for drowsiness;
Cloxacillin Trace amounts in milk; safe in usual dosage; monitor infant
Colchicine Present in milk but no adverse effects reported; caution because of risk of cytotoxicity
Contraceptives, oral Combined oral contraceptives may inhibit lactation-use alternative method of contraception until weaning or for 6 months after birth; progestogen-only contraceptives do not affect lactation (start 3 weeks after birth or later)
Cyclophosphamide Lactation contraindicated during and for
36 h after stopping treatment
Cyclosporine Present in milk-avoid Cytarabine Lactation contraindicated Dacarbazine Lactation contraindicated Dactinomycin Lactation contraindicated
Dapsone Although significant amount in milk risk to infant very small; continue lactation; monitor infant for jaundice
Daunorubicin Lactation contraindicated
Dexamethasone Systemic effects in infant unlikely with maternal dose of less than equivalent of prednisolone 40 mg daily; monitor infant’s adrenal function with higher doses
Diazepam Continue lactation; adverse effects possible; monitor infant for drowsiness;
Didanosine Lactation recommended during first 6 months if no safe alternative to breast milk
Diloxanide Avoid
Doxorubicin Lactation contraindicated
Doxycycline Continue lactation; use alternative drug if possible (absorption and therefore discolouration of teeth in infant probably usually prevented by chelation with calcium in milk)
Efavirenz Lactation recommended during first 6 months if no safe alternative to breast milk
Eflornithine Avoid
Ephedrine Irritability and disturbed sleep reported
Ergocalciferol Caution with high doses; may cause hypercalcaemia in infant
Ergotamine Use alternative drug; ergotism may occur in infant; repeated doses may inhibit lactation
Erythromycin Only small amounts in milk; safe in usual dosage; monitor infant
Ethinylestradiol Use alternative method of contraception; may inhibit lactation; see also Contraceptives, Oral
Etoposide Lactation contraindicated
Fluconazole Present in milk; safe in usual dosage;
monitor infant
Flucytosine Avoid
5-Fluorouracil Discontinue lactation
Fluphenazine Amount excreted in milk probably too small to be harmful; continue lactation; adverse effects possible; monitor infant for drowsiness
Glibenclamide Hypoglycaemia in infant
Haloperidol Amount excreted in milk probably too small to be harmful; continue lactation; adverse effects possible; monitor infant for drowsiness
Halothane Excreted in milk
Hydralazine Present in milk but not known to be harmful; monitor infant
Hydrochlorothiazide Use alternative drug; may inhibit lactation
Hydrocortisone Systemic effects in infant unlikely with maternal dose of less than equivalent of prednisolone 40 mg daily; monitor infant’s adrenal function with higher doses
Ibuprofen Amount too small to be harmful; short courses safe in usual doses
Imipenem + Cilastatin Present in milk-avoid
Indinavir Lactation recommended during first 6 months if no safe alternative to breast milk
Iodine Stop lactation; danger of neonatal hypothyroidism or goitre; appears to be concentrated in milk
Isoniazid Monitor infant for possible toxicity; theoretical risk of convulsions and neuropathy; prophylactic pyridoxine advisable in mother and infant
Ivermectin Avoid treating mother until infant is
1week old
Lamivudine Present in milk; lactation recommended during first 6 months if no safe alternative to breast milk
Levamisole Lactation contraindicated
Levonorgestrel Combined oral contraceptives may inhibit lactation-use alternative method of contraception until weaning or for 6 months after birth; progestogen-only contraceptives do not affect lactation (preferably start 6 weeks after birth or later)
Lithium Present in milk and risk of toxicity in infant; continue lactation; monitor infant carefully, particularly if risk of dehydration
Lopinavir + Ritonavir Lactation recommended during first 6 months if no safe alternative to breast milk
Lumefantrine See Artemether + Lumefantrine
Medroxyprogesterone Present in milk-no adverse effects reported (preferably start injectable contraceptive 6 weeks after birth or later)
Mefloquine Present in milk but risk to infant minimal
6-Mercaptopurine Lactation contraindicated
Metformin Present in milk but safe in usual doses;
monitor infant
Methotrexate Lactation contraindicated
Metoclopramide Present in milk; adverse effects possible;
monitor infant for adverse effects
Metronidazole Significant amount in milk; continue lactation; avoid large doses; use alternative drug if possible
Morphine Short courses safe in usual doses;
monitor infant
Nalidixic acid Continue lactation; use alternative
drug if possible; one case of haemolytic
anaemia reported
Nelfinavir Lactation recommended during first 6 months if no safe alternative to breast milk
Neostigmine Amount probably too small to be harmful; monitor infant
Nevirapine Present in milk; lactation recommended during first 6 months if no safe alternative to breast milk
Nifedipine Small amount in milk; continue lactation;
monitor infant
Nitrofurantoin Only small amounts in milk but could be enough to produce haemolysis in G-6- PD-deficient infants
Norethisterone Combined oral contraceptives may inhibit lactation-use alternative method of contraception until weaning or for 6 months after birth; progestogen-only contraceptives do not affect lactation (preferably start injectable contraceptive
6 weeks after birth or later)
Ofloxacin Continue lactation; use alternative drug if possible
Paracetamol Small amount present in milk: short courses safe in usual dosage; monitor infant
Pentamidine Avoid unless essential
Pentavalent antimony compounds
Avoid
Phenobarbital Continue lactation; adverse effects possible; monitor infant for drowsiness;
Phenoxymethylpenicillin Trace amounts in milk; safe in usual dosage; monitor infant
Phenytoin Small amount present in milk; continue lactation; adverse effects possible; monitor infant for drowsiness;
Potassium iodide Stop lactation; danger of neonatal hypothyroidism or goitre; appears to be concentrated in milk
Povidone–iodine Avoid; iodine absorbed from vaginal preparations is concentrated in milk
Praziquantel Avoid lactation during and for 72 h after treatment; considered safe to continue lactation in treatment of schistosomiasis
Prednisolone Systemic effects in infant unlikely with maternal dose of less than prednisolone
40 mg daily; monitor infant’s adrenal function with higher doses
Primaquine Avoid; risk of haemolysis in G-6-PD- deficient infants
Procainamide Present in milk; continue lactation;
monitor infant
Procarbazine Lactation contraindicated
Promethazine Safe in usual dosage; monitor infant for drowsiness
Propranolol Present in milk; safe in usual dosage;
monitor infant
Propylthiouracil Monitor infant’s thyroid status but amounts in milk probably too small to affect infant; high doses might affect neonatal thyroid function
Pyrimethamine Significant amount-avoid administration of other folate antagonists to infant
Quinidine Significant amount but not known to be harmful
Ranitidine Significant amount present in milk, but not known to be harmful
Ritonavir See Lopinavir with Ritonavir
Salbutamol Safe in usual dosage; monitor infant
Saquinavir Lactation recommended during first 6 months if no safe alternative to breast milk
Senna Avoid; large doses may cause increased gastric motility and diarrhoea
Silver sulfadiazine Continue lactation; monitor infant for jaundice-small risk of kernicterus in jaundiced infants particularly with long- acting sulphonamides, and of haemolysis in G-6-PD-deficient infants
Sodium valproate see Valproic acid
Stavudine Lactation recommended during first 6 months if no safe alternative to breast milk
Sulfadiazine Continue lactation; monitor infant for jaundice-small risk of kernicterus in jaundiced infants particularly with long- acting sulphonamides, and of haemolysis in G-6-PD-deficient infants
Sulfadoxine + Pyrimethamine
Continue lactation; monitor infant for jaundice-small risk of kernicterus in jaundiced infants and of haemolysis
in G-6-PD-deficient infants (due to sulfadoxine)
Sulfamethoxazole + Trimethoprim
Continue lactation; monitor infant for jaundice-small risk of kernicterus in jaundiced infants and of haemolysis
in G-6-PD-deficient infants (due to sulfamethoxazole)
Sulfasalazine Continue lactation; monitor infant
for jaundice-small amounts in milk (1
report of bloody diarrhoea and rashes);
theoretical risk of neonatal haemolysis
especially in G-6-PD-deficient infants
Tamoxifen Suppresses lactation; avoid unless potential benefit outweighs risk
Testosterone Avoid; may cause masculinization in the female infant or precocious development in the male infant; high doses suppress lactation
Tetracycline Continue lactation; use alternative drug if possible (absorption and therefore discolouration of teeth in infant probably usually prevented by chelation with calcium in milk)
Theophylline Present in milk-irritability in infant reported; modified-release preparations preferable
Thiamine Severely thiamine-deficient mothers should avoid lactation as toxic methyl- glyoxal excreted in milk
Trimethoprim Present in milk; safe in usual dosage;
monitor infant
Valproic acid Small amount present in milk; continue lactation; adverse effects possible; monitor infant for drowsiness; (Sodium valproate)
Vancomycin Present in milk-significant absorption following oral administration unlikely
Vinblastine Lactation contraindicated
Vincristine Lactation contraindicated
Warfarin Risk of haemorrhage; increased by vitamin-K deficiency; warfarin appears safe
Zidovudine Lactation recommended during first 6 months if no safe alternative to breast milk

Appendix 7c: Pregnancy

Drugs can have harmful effects on the fetus at any time during pregnancy. It is important to remember this when prescribing for a woman of childbearing age. However, irrational fear of using drugs during pregnancy can also result in harm. This includes untreated illness, impaired maternal compliance, suboptimal treatment and treatment failures. Major congenital malformations occur in 2–4% of all live births, 15% of all diagnosed pregnancies will result in fetal loss. During the first trimester, drugs may produce congenital malformations (teratogenesis), and the greater risk is from third to the eleventh week of pregnancy. During the second and third trimester, drugs may affect the growth and functional development of the fetus or have toxic effects on fetal tissues. Drugs given shortly before term or during labor may have adverse effects on labor or on the neonate after delivery. Few drugs have been shown conclusively to be teratogenic in man but no drug is safe beyond all doubts in early pregnancy. Screening procedures are available where there is a known risk of certain defects.

Prescribing in Pregnancy

Since, approximately 50% of pregnancies are unplanned and rest 50% are planned, if possible, counseling of women before a planned pregnancy should be carried out including discussion of risks associated with specific therapeutic agents, traditional drugs (alternative medicines), over the counter drugs and substances of abuse such as opioids, smoking, alcohol, etc. Drugs should be prescribed in pregnancy only if the expected benefits to the mother are thought to be greater than the risk to the fetus. All drugs should be avoided if possible during the first trimester. Drugs which have been used extensively in pregnancy and appear to be usually safe should be prescribed in preference to new or untried drugs and the smallest effective dose should be used. Keeping in view the prevalence of irrational polypharmacy, emphasis should be laid on promoting the use of well-known single component drugs to multicomponent drugs. Since, there does appear to be an association of very potent topical corticosteroids with low birth weight, even the dermatological drug products being used should be cautiously selected and used.
The pronounced and progressive change in drug disposition that occurs during pregnancy is another major reason which calls for attention. Major physiological changes which influence drug disposition in mother and fetus are:
e
4. Increased cardiac output
in mother
5. Presence of placental
barrier
6. Drug metabolizing enzymes activity in fetal liver is very low
Increased renal blood flow and glomerular filtration and hence, increased elimination of drug
Selectivity of drug permeation based on its hydrophobicity or molecular weight of drug
Slow elimination of drugs by fetus
Though maternal medication carry the risk of increase in the incidence of abortion, stillbirths, fetal death, premature or delayed labor or create perinatal problems; but certain medications like folic acid are recommended for all pregnant women to reduce the rate of congenital anomalies specifically, the neural tube defect.
The Food and Drug Administration has categorized the drug risks to the fetus that runs from: “Category A” (safest) to “Category X” (known danger--do not use!)

Category A

Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.

Category B

Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal- reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).

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.

Category D

There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Category X

Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Appendix 7d: Renal Impairment

Dosing considerations in renal impairment

The number of patients with chronic kidney disease (CKD) and reduced renal function have been inexorably increasing. Reduced renal function may need adjustment in drug therapy as kidney plays a major role in the pharmacokinetics of a large number of drugs.

• Renal insufficiency frequently alters drug distribution volume. Edema and ascites increase the apparent volume of distribution of highly water-soluble or protein-bound drugs. Usual doses of such drugs given to edematous patients result in inadequate, low plasma levels.

• The alteration of plasma protein binding in patients with renal insufficiency is an important factor affecting both efficacy and toxicity. In patients with uremia the unbound fraction of several acidic drugs is substan- tially increased which may lead to serious toxicity.

• Although renal insufficiency is thought to affect primarily the renal elimination of drugs or metabo- lites, renal failure substantially affects drug biotrans- formation. Uremia slows the rate of reduction and hydrolysis reactions.

• Many active or toxic metabolites are produced during drug metabolism. Many of these metabolites depend on the kidneys for their removal from the body. The accumulation of active metabolites can explain in part the high incidence of ADRs seen in renal failure.

A few points should be kept in mind while prescribing;

• Renal function declines with age so that by the age of

80 it is half that in healthy young subjects.

• It is advisable to determine renal function not only before but also during the period of treatment and adjust the maintenance dose as necessary.

• One should try to keep drug prescription to minimum.

• Nephrotoxic drugs should, if possible, be avoided in all patients with renal disease because the nephrotox- icity is more likely to be serious.

• One should stay alert for unexpected ADRs.

The recommendations in the table below are meant only as a guide and do not imply efficacy or safety of a recommended dose in an individual patient.

A loading dose equivalent to the usual dose in patients with normal renal function should be considered for drugs with a particularly long half-life.

The table below gives the common drugs where in renal impairment dose adjustment is required.

When the dose method (D) is suggested, the percentage of the dose for normal renal function is given and when the interval method (I) is suggested, the actual dose interval is provided.

Drug

Dose

Method

GFR >50 (ml/ min)

GFR 10-50

(ml/min)

GFR <10

(ml/min)

CAPD

HD

Acetaminophen

I

q4h

q6h

q8h

Dose as

GFR < 10

Dose as

GFR < 10

Acetazolamide

I

q6h

q12h

Avoid

No data

No data

Acetylsalicyclic

Acid

I

Q4h

Q4-6h

Avoid

As normal

GFR

As normal GFR dose post HD

Acyclovir

D, I

5 mg/kg q8h

5 mg/kg q12-24h

2.5 mg/kg

q24h

Dose as

GFR < 10

Dose as GFR < 10 dose post HD

Allopurinol

D

75%

50%

33%

Dose as

GFR < 10

Dose as

GFR < 10

Amikacin

D, I

60–90%

q12h

30–70%

q12–18h

20–30%

q24–48h

15–20 mg

/L/day

5 mg/kg

post HD

Amiloride

D

100%

50%

Avoid

NA

NA

Aminophylline

D

100%

200–400

mg q12h

200–300 mg q12h

Dose as

GFR < 10

Dose as

GFR < 10

Amphotericin B

I

q24h

q24h

q24-36h

Dose as

GFR < 10

Dose as

GFR < 10

Ampicillin

I

q6h

q6–12h

q12-24h

Dose as

GFR < 10

Dose as

GFR < 10

Cefazolin

I

q8h

q12h

q24–48h

0.5 g q12h

0.5–1.0 g

post HD

Cefixime D 100% 75% 50% 200 mg

q24h

200 mg

q24h

dose post

HD

Cefotaxime I 100%

q8h

100% q8h 50%

q8–12h

1 g q24h Dose as GFR < 10 dose post HD

Chloroquine D 100% 100% 50% Dose as

GFR < 10

Ciprofloxacin D 100% 50-75% 50% 250 mg q8h

Cisplatin D 100% 75% 50% Dose as

GFR < 10

Dose as

GFR < 10

250 mg

q12h

Dose as

GFR < 10

Cyclophospha- mide

D 100% 75-100% 50-75% Dose as

GFR < 10

Dose as

GFR < 10

Dapsone 100% 100% 50% Dose as

GFR < 10

Didanosine I 100% 50% 25% Dose as

GFR < 10

Dose as

GFR < 10

Dose as

GFR < 10

Digoxin D, I 100%

q24h

25–75%

q36h

10–25%

q48h

Dose as

GFR < 10

Dose as

GFR < 10

Enalapril D 100% 75-100% 50-75% Dose as

GFR < 10

Erythromycin D 100% 100% 50-75% Dose as

GFR < 10

Ethambutol I q24h q24-36h q48h Dose as

GFR < 10

Etoposide D 100% 75% 50% Dose as

GFR < 10

Fentanyl D 100% 75% 50% Dose as

GFR < 10

Fluconazole D 100% 100% 50% Dose as

GFR < 10

Dose as

GFR < 10

Dose as

GFR < 10

Dose as GFR < 10 dose post HD

Dose as

GFR < 10

Dose as

GFR < 10

Dose as GFR < 10 dose post HD

Gentamicin D, I 60–90% 30–70%

20–30%

3–4 mg/L/

Dose as

q8–12h

q12h

q24–72h

day

GFR < 10 dose post HD

Isoniazid D 100% 100% 75% Dose as

GFR < 10

Dose as GFR < 10 dose post HD

Lamivudine D, I 100% 50–150

mg qd

25 mg qd Dose as

GFR < 10

Dose as GFR < 10 dose post HD

Metformin D 50% Avoid Avoid Avoid Avoid

Metoclopra- mide

D 100% 75% 50% Dose as

GFR < 10

Dose as

GFR < 10

Penicillin G D 100% 75% 20-50% Dose as

GFR < 10

Dose as

GFR < 10

Pyrazinamide D 100% As normal

GFR

As normal

GFR

As normal

GFR

As normal

GFR

Quinine I q8h q8-12h q24h Dose as

GFR < 10

Streptomycin I q24h q24–72h q72h 20–40 mg

/L/day

Dose as GFR < 10 dose post HD

750 mg

2–3/

week

Triamterene I q12h q12h Avoid Avoid Avoid

Tubocurarine D 75% 50% Avoid Unknown Unknown

Vancomycin D, I 500 mg q6-12h

500 mg q12-48h

500 mg q48-96h

Dose as

GFR < 10

Dose as

GFR < 10

Zidovudine

(AZT)

D, I 100%

q8h

100% q8h 50% q12h Dose as

GFR < 10

Dose as

GFR < 10

HD: Hemodialysis; CAPD: Chronic Ambulatory Peritoneal

Dialysis.