Any drug my produce unwanted or unexpected adverse reaction. Detection, recording and reporting of these reactions is of vital importance. Doctors, pharmacists and nurses have the responsibility to participate in this programme. Adverse reactions are significant cause of morbidity, mortality and can affect adherence to treatment schedule and increase risk of resistance and relapse of disease.
ARV drugs have low safety profile and given the facts a) they need to be taken on chronic basis, b) they are consumed by patients who are immuno-deficient, and c) immuno-deficient patients are more prone to develop adverse reaction to any drug. Hence it is of paramount importance that patients receiving ARV drugs or other drugs are closely monitored for ADRs and they are managed appropriately so that adherence to the prescribed treatment is ensured.
Aims:
- To discuss most commonly occurring ADRs to ARV and OI drugs
- To discuss the process of detection, reporting and managing ADRs
Objectives: By the end of session –
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DEFINITIONS
Adverse Drug Reaction (ADR) Adverse drug reaction is a response to a medicine which is noxious and unintended and which occurs at doses normally used in man (WHO).
Adverse Event An adverse event is defined as any untoward medical occurrence that may be present during treatment with a medicine but which does not necessarily have causal relationship with this treatment (WHO).
Side Effect. It is any unintended effect of medicine occurring at doses normally used in patients and that is related to pharmacological properties of the drug (WHO).
Pharmacovigilance. It is defined as the science and activities relating to the detection, assessment, understanding and prevention of ADR or any other possible drug related problems (WHO).
During the last decades, it has been demonstrated by a number of studies that medicine morbidity is one of the major health problems. It has been estimated that ADR are the fourth to sixth largest cause for mortality in United States of America. The percentage of of hospital admissions due to ADR in some western countries is more than 10% approximately. There is very limited information available on ADRs in developing countries. It has been estimated that 30 t0 50% ADRs are preventable.
Types of ADR
ADRs have been broadly classified into:
1. Type A (Augmented) Reaction: also known as “side effects”, are those reactions related to the exaggerated pharmacological effects of the drugs and tend to be fairly common (usually more than 1 in 100), dose related (more frequent and more severe at higher dosage) and may often by avoided by using dosages that are appropriate for the individual patients e.g., hypoglycemia with insulin, constipation with morphine. Type A reactions are usually predictable and reproducible.
2. Type B (Bizarre) Reactions: are those that are unexpected and unpredictable and often related to patient factors like genetic predisposition, allergy etc. they occur in a minority of the patients (say less than 1 per 100), are often serious, may show little or no relationship with dosage and may be difficult to detect. These reactions are unpredictable.
3. Type C (Chronic) Reactions: which are due to long term use of a drug, e.g., tardive dyskinesia with neuroleptics, analgesic nephropathy etc.
4. Type D (Delayed) Reactions: e.g., teratogenesis, carcinogenesis like clear cell carcinoma of the female reproductive tract in mature women whose mothers have received diethylstilbestrol during pregnancy.
Major Aims of Pharmacovigilance
- Early detection of ADR.
- Identification of risk factors and possible mechanism underlying adverse reaction.
- Prevention of ADRs and making treatment as safe as possible.
- Educating and informing patient.
Why Post Marketing Surveillance and Reporting ADR is Needed?
The information collected during pre-marketing phase of drug development is inevitably incomplete with regard to possible ADRs. This is mainly because:
- Tests in animals are insufficient to predict human safety.
- Patients used in clinical trails are selected and limited in number, the conditions of use differ from those in clinical practice and the duration of trials is limited.
- By the time of licensing, exposure of less than 5000 human subjects to a drug allows only the more common ADR to be detected.
- At least 30,000 human beings need to be treated with a drug to be sure that you do not miss at least one patient with an ADR which has an incidence of 1 in 10,000 exposed individuals.
- Information about rare but serious adverse reactions, chronic toxicity, use of special groups (such as children, the elderly or pregnant women) or drug interactions is often incomplete or not available.
Why Pharmacovigilance is Needed in Every Country?
There are differences among countries (and even regions within countries) in occurrence of ADRs and other drug-related problems. This may be due to differences in e.g. –
1. Diseases and prescribing practices.
2. Genetics, diet, traditions of people.
3. Drug manufacturing processes used which influence pharmaceutical quality and composition.
4. Use of traditional and complementary drugs (e.g., herbal remedies), which may pose specific toxicological problems, when used alone, or in combination with other drugs.
ADRs with Antiretroviral Drugs
Adverse effects have been reported with all antiretroviral drugs and are among the most common reason for switching or discontinuing therapy as well as medication non-adherence. The incidence of ADRs with newer antiretroviral regimens is generally declining now (less than 10%).
Several factors may predispose individuals to certain antiretroviral associated ADRs viz., women seem to have higher propensity of developing “Steven-Johnson Syndrome” and “Symptomatic Hepatic” events with nevirapine and high rate of lactic acidosis with NRTIS. Other factors include concomitant use of medication, co-morbid condition co-infections, drug-drug interactions or generic predisposition viz., abacour hypersensitivity reaction.
Although therapeutic goals of antiretroviral therapy include achieving, maintaining viral suppression and improving patient immune function, an overarching goal should be to select a regiment that is not only effective but is also safe. This requires taking into account an individual patient’s underlying conditions, concomitant medication and history of drug intolerance.
Adverse Drug Reactions to Individual Antiretroviral Drugs
Lamivudine: It is relatively safe ARV drug. Potential ADRs are related to CNS viz. headache, insomnia, fatigue and gastrointestinal discomfort. They are mild in nature.
Monitor patient’s complete blood count (CBC), platelet count, renal function and liver functions to detect and exclude liver, blood, pancreas toxicity.
Stavudine: The major dose limiting toxicity is dose related peripheral sensory neuropathy. The incidence increases when stavudine is given with other neuropathy inducing agents viz., didanosine. Most of the time symptoms resolve with discontinuation of therapy.
Other potential adverse effects viz., pancreatitis, arthralgia, increased serum aminotransferase, lactic acidosis, fat atrophy appear to occur more frequently in patients receiving stavudine than other NRTIS.
Patients should be taught to report signs and symptoms of neuropathy viz., pain burning, aching, weakness or pin and needles in limbs.
Monitor CBC, liver functions, and kidney functions.
Zidovudine: The most common adverse effect of zidovudine is myelo-suppression resulting into macrocyctic anemia or neutropenia (2 – 8%). Gastrointestinal intolerance, headaches, insomnia may occur but tend to resolve during therapy. Other less frequent ADRs are thrombocytopenia and myopathy.
Monitor CBC, renal and liver functions regularly.
Efavirenz: Most common adverse effects of efavirenz involve central nervous system, dizziness drowsiness, headache, confusion, amnesia, depression, and nightmare. They occur in 50% of cases. However, they tend to resolve after first month of treatment. Skin rashes have also been reported in 28% cases (mild to moderate in nature) tend to resolve despite continuation of therapy. Elevation of liver enzymes, increase in total serum cholesterol has been observed in 10-20% cases.
Monitor CBC, Liver function test and cholesterol levels.
Nevirapine: Skin rashes are the most common ADRs reported with nevirapine. Dose should be escalated slowly to decrease incidence of skin rashes. Women may have greater propensity and sometimes may develop life threatening Steven- Johnson syndrome. Hepatitoxicty has been observed in 4% cases.
Antiretroviral alone or in combination have been linked to lactic acidosis and hepatitoxicty. It warrants regular monitoring. Antiretroviral have been linked to accumulation and redistribution of body fat resulting a central obesity peripheral wasting and development of buffalo hump.
Monitor liver function and renal function before starting therapy and at regular intervals.
Minor and Major ADRs to First Line Regimens
(A) d4T + 3TC + NVP
Minor ADRs: Insomnia, nausea, diarrhea, headache, fatigue, abdominal discomfort, and mild rashes.
Major ADRs:
(a) Neuropathy, fat changes, pancreatitis, lactic acidosis, (presented as fatigue and cough) with Stavudine.
(b) Liver toxicity, severe skin rashes, fever with Nevirapine.
(B) d4T + 3TC + EFV
Minor ADRs: Somnolence, insomnia, confusion, nightmare, dizziness, nausea, diarrhea, headache, fatigue, and rash.
Major ADRs:
(a) Neuropathy, fat changes, lactic acidosis, and pancreatitis with Stavudine.
(b) Liver toxicity and severe skin rashes with EFV.
(C) AZT + 3TC + NVP
Minor ADRs: Nausea, diarrhea, headache, fatigue and mild rashes.
Major ADRs:
(a) Severe anemia, lactic acidosis and myalgia with Zidovudine.
(b) Severe rashes with Nevirapine.
(c) Liver toxicity with NVP + AZT.
(D) AZT + 3TC + EFV
Minor ADRs: Nausea, diarrhea, headache, fatigue, somnolence, insomnia, confusion, nightmare and dizziness.
Major ADRs:
(a) Severe anemia, myalgra and lactic acidosis with ZDV.
(b) Severe rashes, severe confusion, psychosis and depression with EFV.
For all minor adverse effects, it is important that patients may be told and prepared to cope up. However, major adverse drug effects must be reported to treating doctors as they may be serious and would require further investigations or switch over to other regimen.
Pharmacist should be able to detect ADRs and minor change in patient’s disease state or development of any other new symptoms should not be ignored. The culture of reporting ADRs should be inculcated. All ART centers should have pharmacovigilance cell. All ADRs reported should be analyzed as per WHO guidelines of causal assessment.
Common Adverse Drug Reactions to Drugs Used in OI
Cotrimoxazole: The ADRs are due to both trimethoprim and sulphamethoxazol. Most common ADRs are nausea, vomiting, drug fever, drug rash, headache, seizures, leucopenia and granulocytopenia.
Patients with AIDS and pneumocystis pneumonia have a particularly high frequency of ADR. One should promptly report rash, sore throat, fever, and mouth sores. They are early signs of erythema multiforme, which may progress to sometime Steven-Johnson syndrome.
Ciprofloxacin: it is relatively well tolerated drug. Most common effects are nausea, vomiting, diarrhea, insomnia, skin rashes, sometime seizures, arthralgia. Tendon rupture has been reported occasionally.
Levofloxacin: Besides gastrointestinal and CNS ADRs as reported with ciprofloxacin, additional ADRs viz., hypoglycemia as well as hyperglycemia, prolongation of QTc interval have been reported occasionally. Caution need to be observed in patients with diabetes and any heart ailment.
Azithromycin: It is very well tolerated drug; may cause sometime mild gastric upset, abdominal pain, headache and dizziness. However, after addition of this drug to ARV therapy, any new symptoms reported by patients should be considered seriously.
Clindamycin: Common ADRs are diarrhea and skin rashes. Impaired liver functions (with or without jaundice) and neutropenia sometimes occur. Most serious ADR is severe diarrhea and entrocolitis have been reported. The enterocolitis is due to clostridium difficile superinfection that may be fatal. Therefore, patient receiving clindamycin should be closely monitored and in case develops enterocolitis; this drug should be immediately stopped.
Amoxicillin + Clavulanic Acid: It is relatively safe drug, mild to moderate skin rashes, gastrointestinal disturbance may be reported.
Cefotaxime
Generally more toxic than penicillin. Most common are hypersensitivity reaction viz. skin rashes, angioedema, asthma, sometime anaphylasis reactions can occur.
Sulfadiazine
Common ADR is crystalluria (dose-related), nausea, vomiting and epigastric pain, hypersensitivity reactions. Patient should be advised to take lot of fluids while taking sulfadiazine.
Clarithromycin
Gastric tolerance is better than erythromycin. Occasional reports of hepatic dysfunction, pseudo membranous enterocolitis, rhabdomylosis have been noted.
Fluconazole: It is relatively safe drug. The most common adverse reactions are minor gastrointestinal upset viz., nausea, vomiting, abdominal pain, rashes and headache. Causing abnormalities in liver enzyme and clinical hepatitis have rarely been reported.
Itraconazole
It is well tolerated. Gastric intolerance, headache and hypokalemia are most common adverse effects observed.
Amphotericin B (AMB)
Toxicity of AMB is high. With each infusion, there is fever, chills, aches and pain. Nephrotoxicity is very common. Thrombophlebitis of the infected vein is also seen.
Acyclovir: When given orally, the drug is well tolerated. It may cause nausea, headache, malaise and sometimes CNS effects.
When applied locally, it may cause stinging and burning sensation after each application.
I/V administration may cause rashes, fall in B.P and emesis. It is reported to cause dose dependent, kidney function deterioration and neurological manifestation.
Ganciclovir
Causes rash, fever, bone marrow depression, neuropsychiatric disturbances. Its use is restricted to CMV infection only. It should not be given with zidovudine as both will have additive effect on bone-marrow depression.
Metronidazole: ADRs to metronidazole are relatively frequent and unpleasant but mostly non-serious.
Most common ADRs are anorexia, nausea, bitter or metallic taste, abdominal cramps and looseness of stool.
Less frequent ADRs are headache, glossitis, dryness of mouth, rashes and neutropenia (transient). Prolonged use may cause peripheral neuropathy and CNS effects.
Nitazoxanide
Relatively better tolerated. Main ADRs are headache, abdominal pain, diarrhea, nausea and vomiting.
Albendazole: It is well tolerated drug. Gastrointestinal effects are reported viz., nausea and distention of abdomen. It may be of concern in children.
Note:
While discussing ADRs to drugs used in OI, ADRs reported are in individuals other than AIDS patients. It may be noted that whenever it is mentioned that ADRs are minor and well tolerated, it may not be same in AIDS patients as they are immuno-deficient patients and they tend to develop some minor ADRs also of moderate to severe intensity. It is, therefore, very essential to closely monitor all ADRs in these cases.
Key Learning Points
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ACTIVITY
A 40 year old male patient diagnosed as suffering from HIV infection. He was prescribed first-line ARV therapy, which included Nevirapine 200mg + Lamivudine 150mg + Stavudine 30 mg twice a day.
Initially, patient experienced minor symptoms of nausea and dyspepsia. However, in subsequent visit, patient complained of discolouration of urine.
What will be your line of action? Fill in the attached ADR Reporting Card to be submitted to your higher centre.
SUSPECTED ADVERSE DRUG REACTION REPORT CARD
If you suspect that an adverse reaction is related to a drug, or a combination of drugs, you should fill this form and report all suspected reactions to Higher Centre as early as possible.
PATIENT’S DETAILS Patient’s Initials -------------------------- Sex: (M\ F) --------Weight if known (kg)---------- Age (at time of reaction) ------------------- Identification (ART Regn, No) ---------------------- Date of reporting ADR --------------- |
SUSPECTED DRUG (S) Give generic / brand name of drug : Batch number if known Route Dosage Date & Time Started --------------------------- -------- --------------- ------------------- ---------------------------. -------- --------------- -------------------- --------------------------- --------- ---------------- --------------------- |
Describe the ADR |
Concomitant Medication administered:
1-------------------------------------4-------------------------------------------- 2-------------------------------------5--------------------------------------------
3-------------------------------------6--------------------------------------------
Please ensure the form is completely filled
Signature of the reporting Pharmacist……….Signature of the reporting DOCTOR……….
Date: --------------------------------- Date:-------------------------------
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