6 курс / Кардиология / Kartikeyan_HIV and AIDS-Basic Elements and Properties
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Dosage Forms and Dosage
The drug is available as oral solution containing 1 mg per mL and as 15, 20, 30, or 40 mg capsules. For persons weighing more than 30 kg, the dose is 30 mg twice a day. The maximum dose (more than 60 kg) is 40 mg twice daily (Harries et al., 2004). The dosage should be reduced in persons with renal insufficiency (Lewin et al., 1997). The capsules may be opened and mixed with small amounts of food. There are no food restrictions during treatment (Fact Sheet 401, 2006).
Storage Requirements
The oral solution should be stored under refrigeration and shaken well before use. The capsules should be stored in glass bottles (Harries et al., 2004).
Side Effects
The drug should not be used with ZDV or ddI (Fact Sheet 401, 2006). The patient should be warned about early signs of peripheral neuropathy and those with a past history of this condition (particularly after taking ddI or ddC) have a high risk of recurrence. Peripheral neuropathy is reversible if treatment is stopped. Headache and nausea may occur and decrease with continued treatment. Though pancreatitis is rare, past history of pancreatitis, or risk factors for this condition (ganciclovir or pentamidine therapy) should be elicited. Anaemia and neutropenia are infrequent side effects (Lewin et al., 1997). Chills, fever, and diarrhea have also been reported (Fact Sheet 401, 2006).
Monitoring During Therapy
During d4T therapy, it is necessary to monitor the peripheral nervous system, complete blood count, liver function tests, and serum amylase levels. The dose must be reduced or the drug should be withdrawn if signs of peripheral neuropathy develop or if serum amylase level is more than twice normal (Lewin et al., 1997).
[F] ABACAVIR (ABC)
Dosage Forms and Dosage
The drug is available as oral solution (20 mg/mL) and 300 mg tablets. The dose is 8 mg per kg body weight for patients younger than 16 years or less than 37.5 kg. For those older than 16 years or weighing more than 37.5 kg, the dose is 300 mg twice daily. The drug may be administered along with food and there are no food restrictions. An FDC of ZDV 300 mg + 3TC 150 mg + ABC 300 mg is available as Trizavir. The maximum dose (those weighing more than 40 kg) of this FDC is one tablet twice daily. The tablet cannot be split and therefore, for children
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weighing less than 30 kg, Trizavir cannot be dosed accurately. At present liquid preparations of Trizavir are not available (Harries et al., 2004).
Side Effects
Patients must be warned about possible hypersensitivity reaction, which occurs in about 8 per cent of patients (Fact Sheet 401, 2006). If hypersensitivity reaction occurs, ABC should be stopped permanently (Harries et al., 2004). ABC should not be co-administered with 3TC or TDF (Fact Sheet 401, 2006).
[G] EMTRICITABINE (FTC)
The adult dose of the drug is 200 mg once daily. There are no food restrictions. The side effects include headache, nausea, vomiting, and skin rash (Fact Sheet 401, 2006). A FDC of EFV, emtricitabine, and TDF disopril fumarate called Atripla has been approved for use in HIV-1 infected adults by the FDA (USA) in July 2006. Atripla is the first once-pill, once-a-day ARV product (FDA, 2006).
[H] “NUKES” UNDER DEVELOPMENT
ELVUCITABINE (ACH-126, 443, beta-L-Fd4c) is an once-daily drug, which has shown activity against HIV that is resistant to several other “nukes” and is also effective against HBV.
MIV-210 (FLG) has shown activity against HIV that is resistant to several other “nukes”.
RACIVIR has shown activity against HIV and HBV in laboratory studies. The drug exhibited anti-HIV activity that lasted more than 2 weeks after the drug was stopped. Probably, racivir can be used as a once-daily drug (Fact Sheet 410, 2006).
APRICITABINE (AVX 754, formerly SPD 754) has shown good activity against 3TC-resistant HIV and seems well tolerated.
AMDOXOVIR (MPD) is in Phase II studies and ocular problems detected in early studies are under investigation.
DIOXOLANE THYMIDINE (DOT) is being studied in the University of Georgia, USA.
KP1461 induces lethal mutations in HIV (Fact Sheet 410, 2006).
APPENDIX 3
NON-NUCLEOSIDE RTIs (NNRTIs)
These drugs (also called “non-nukes”), actually bind to reverse transcriptase and prevent its functioning. All “non-nukes” interact with many other drugs and therefore, the physician should elicit the medication history before starting
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treatment and advise the patient to seek advice before taking any medication. NOTE – The dose of each drug may vary if ARV drugs are combined.
[1] NEVIRAPINE (NVP)
Pharmacology
On oral administration, the bioavailability is 90 per cent. The serum half-life is 25–30 hours. NVP is metabolized by cytochrome P450. Almost 80 per cent of the ingested dose is excreted in urine as glucuronide, 5 per cent is excreted unchanged in urine, and 10 per cent is excreted in faeces. 12 months of triple drug therapy (NVP, ddI, and ZDV) causes significant decrease in viral load. Monotherapy or dual therapy with ZDV is associated with rapid development of drug resistance (Lewin et al., 1997).
Dosage Forms and Dosage
NVP is available as oral suspension containing 10 mg per mL and as 200 mg tablets. The drug can be given along with food and there are no food restrictions (Fact Sheet 401, 2006). Since initiation of full-dose therapy is associated with development of skin rash in up to 50 per cent of patients, incremental doses are given as mentioned in Table 3.
Storage Requirements
Oral suspension can be stored in room temperature (up to 25°C or 77°F); must be shaken well before use (Harries et al., 2004).
Side Effects and Interactions
Fever, headache, and nausea have been reported (Fact Sheet 401, 2006). Hepatitis may occur in 1 per cent of cases. Steven-Johnson syndrome is rare, but the risk is increased on ingestion of drugs containing clavulanic acid. The drug induces (stimulates) cytochrome P450 enzyme. Since rifampicin, rifabutin, antiepileptics, oral contraceptives, and other protease inhibitors reduce the plasma levels of NVP, these drugs should not be co-administered (Collier et al., 1996).
Table 3. Incremental dosage for nevirapine (Harries et al., 2004)
Age |
First 2 weeks |
Next 2 weeks |
Thereafter |
|
|
|
|
15–30 days |
5 mg per kg once daily |
120 mg per m2 twice |
200 mg per m2 |
|
|
daily |
twice daily |
30 days to 13 years |
120 mg per m2 once |
120–200 mg per m2 twice |
|
|
daily |
daily |
|
>13 years |
200 mg once daily |
200 mg twice daily |
|
|
|
|
|
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Monitoring during Therapy
Liver enzymes should be monitored during NVP therapy since abnormal liver function tests are common (Lewin et al., 1997). Patients should be warned about skin rash. If mild or moderate rash occurs, the drug is withheld and dosing is restarted from the beginning of dose escalation. In case of severe rash, NVP is to be discontinued (Harries et al., 2004).
[2] –DELAVIRIDINE (DLV)
Pharmacology
On oral administration, the bioavailability is 85 per cent. The serum half-life is 5–8 hours. The drug is metabolized partially by cytochrome P450. Of the ingested dose 51 per cent is excreted in urine as metabolites, 5 per cent is excreted unchanged in urine, and 44 per cent in faeces (Lewin et al., 1997).
Dosage Forms and Dosage
This drug is available as 100 mg tablets. The adult dose is 100–300 mg four times a day. Antacids and ddI should be avoided within 1 hour of administering the drug, but there are no food restrictions (Fact Sheet 401, 2006). Delaviridine (DLV) should be used only in combination with other ARV drugs. Triple drug therapy (DLV, ddI, ZDV) is used (Lewin et al., 1997).
Side Effects and Interactions
Diffuse maculopapular skin rash may develop in up to 30 per cent of patients. Mild headache, nausea, vomiting, diarrhea, and fatigue have been reported with its use (Fact Sheet 401, 2006). Liver enzymes may be elevated and hence, liver functions should be monitored (Lewin et al., 1997). DLV inhibits cytochrome P450 enzyme and interacts with multiple drugs. Drugs that decrease levels of DLV, thus increasing risk of therapeutic failure of DLV include phenobarbital, phenytoin sodium, rifabutin, and rifampicin. On the other hand, DLV increases blood levels causing potential toxicity of the following drugs if co-administered – clarithromycin, dapsone, ergot alkaloids, IDV, quinidine, saquinavir, and warfarin (Lewin et al., 1997). Terfenadine, astemizole, alprazolam, midazolam, and cisapride should also not be co-administered with DLV (Lewin et al., 1997).
[3] EFAVIRENZ (EFV)
This NNRTI is recommended only for children aged over 3 years. The drug is available as syrup containing 30 mg per mL and as capsules in the strengths of 50, 100, and 200 mg (Table 4).
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Table 4. Dosage of efavirenz (Harries et al., 2004)
Weight of child (kg) |
Capsule (liquid) dose* |
10–15 |
200 mg (270 mg = 9 mL) once daily |
15–20 |
250 mg (300 mg = 10 mL) once daily |
20–25 |
300 mg (360 mg = 12 mL) once daily |
25–33 |
350 mg (450 mg = 15 mL) once daily |
33–40 |
400 mg (510 mg = 17 mL) once daily |
>40 |
600 mg once daily |
* The syrup requires higher doses than capsules.
EFV is best given at bedtime, especially in the first 2 weeks, to avoid side effects pertaining to the central nervous system. The drug can be coadministered with food, but high-fat meals increase absorption by 50 per cent. The capsules may be opened and added to food and the very peppery taste of the drug can be disguised by mixing with sweet foods or jam (Harries et al., 2004). Side effects include vivid dreams, insomnia, anxiety, dizziness, skin rash, nausea, diarrhoea, and headache (Fact Sheet 401, 2006).
[4] “NON-NUKES” UNDER DEVELOPMENT
(+)-CALANOLIDE A is derived from a rainforest plant. It can easily cross the blood-brain barrier and remain the blood stream for a long time.
GW5634 (also known as 695634) is a precursor that is broken down in the body to produce GW 8248 that has better bioavailability. It can cause skin rash and elevate levels of liver enzymes.
MIV-150 has shown activity against HIV strains that are resistant to other “non-nukes” in laboratory studies (Fact Sheet 430, 2005).
ETRAVIRINE (TMC 125) and TMC 278 have exhibited activity against some HIV strains that are resistant to other “non-nukes”.
BILR 355 BS is being developed against wild-type and NNRTI-resistant HIV. CAPRAVIRINE (AG 1549, formerly S-1153) has shown disappointing
results in a recent Phase II trial (Fact Sheet 430, 2005).
APPENDIX 4
PROTEASE INHIBITORS
These ARV agents target the HIV enzyme protease, which cleaves the gag polyprotein that is required for production of mature, infectious virions. PIs also inhibit viral assembly. Nausea and diarrhoea are common with PIs. Bulking agents, loperamide, and dietary modifications can be helpful for diarrhoea (Wig, 2002). All PIs interact with many other drugs and therefore, the physician should elicit the medication history before starting treatment and advise the
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patient to seek advice before taking any medication. Drugs decreasing blood levels of PIs, causing their potential therapeutic failure include carbamazepine, NVP, phenobarbital, and rifampicin. PIs increase the blood levels of alprazolam, midazolam, triazolam, astemizole, terfenadine, cisapride, tricyclic antidepressants, felodepine, nifedipine, lovastatin, simvastatin, clarithromycin, cyclosporin A, and diazepam (Lewin et al., 1997).
[A] NELFINAVIR (NFV)
The drug is available as 250 mg tablets and as powder for oral suspension, to be mixed with liquid before administration. Each 5 mL level teaspoonful of the suspension contains 200 mg. The powder is faintly bitter; gritty and hard to dissolve. The drug is to be taken with meals or a snack (Fact Sheet 401, 2006). Administration along with acidic food or juice increases its bitter taste (Table 5).
The tablets can be halved, or crushed and added to food or dissolved in water. Because of difficulties in dissolving the powder, crushed tablets are preferred even for infants if appropriate dose can be given. Powder and tablets can be stored at room temperature (Harries et al., 2004). Side effects include nausea, diarrhoea, flatulence, abdominal pain, and weakness (Fact Sheet 401, 2006).
[B] INDINAVIR (IDV)
Pharmacology
This drug is indicated in HIV-infected adults. On oral administration, the bioavailability is 30 per cent. The serum half-life is 1.5–2 hours. IDV is effective when used alone and it exhibits synergistic ARV activity with ZDV, ddI, and NNRTIs. Undetectable viral loads have been achieved with triple therapy (IDV, ZDV, 3TC) in 88 per cent of patients (Lewin et al., 1997).
Dosage Forms and Dosage
IDV is available as 200 and 400 mg tablets and should be stored in cool, dry place. The recommended standard dose is 800 mg every 8 hours (not three times a day), to be taken 1 hour before or after meals, or with low-fat snack or with lots of water on empty stomach (Fact Sheet 401, 2006). Patients should be advised to avoid consuming grape fruit and its juice altogether when taking certain medicines
|
Table 5. Dosage of nelfinavir (Harries et al., 2004) |
|
|
Age |
Dose |
|
|
<1 year |
40–50 mg per kg body weight three times daily (or) 75 mg per kg twice daily |
1–13 years |
55–65 mg per kg body weight twice daily |
>13 years |
1,250 mg twice daily |
|
|
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such as IDV because the interacting effect may persist for up to 3 days after ingestion (ADRAC, 2003). IDV should be started in full standard dose if liver functions are normal. Dosage must be reduced in cases of liver impairment. Liver function tests should be monitored during IDV therapy (Lewin et al., 1997).
Side Effects
Patients should be advised to consume at least 1.5 L of fluid daily to reduce risk of nephrolithiasis, which may occur in 2–5 per cent of cases due to poor solubility of IDV in urine. Other toxic effects include headache, nausea, abdominal pain, skin rash, dry skin, pharyngitis, and alteration of taste. Dose-dependent hyperbilirubinemia and elevated levels of serum transaminases may occur and these decrease with reduction in dosage. Oesophageal reflux is seen in 3 per cent of cases. Since antacids prevent absorption of IDV, reflux should be treated with H2 blockers and proton-pump inhibitors (Wig, 2002).
Drug Interactions
IDV, which is metabolised by cytochrome P450 isoenzyme CTP 3A4, interacts with drugs that induce or inhibit this enzyme. The drug should not be administered within 1 hour of ddI. Co-administration of the following drugs are to be avoided – astemizole, terfenadine, cisapride, triaxolam, midazolam, ergot alkaloids, and itraconazole. With ketoconazole treatment, the dose of IDV should be reduced to 600 mg three times a day. Use of rifampicin should be avoided for treatment of mycobacterial infections. If rifabutin is used, the standard dose of IDV should be halved (Lewin et al., 1997).
[C] RITONAVIR (RTV)
Pharmacology
RTV is metabolised by cytochrome P450 isoenzymes 3A4, 2D6, 2C9, and 2C10. Thus, it interacts with multiple drugs and a checklist (Table 6) should be used when any drug is being prescribed to patients on RTV therapy. Serum half-life is 3–5 hours (Lewin et al., 1997). When RTV is used in small doses to boost the action of other PIs, the name of the drug is suffixed with “/r”. For example, SQV/r means saquinavir boosted with RTV.
Dosage Forms and Dosage
This drug is available as 100 mg capsules. It is indicated in HIV-infected patients older than 12 years of age. The recommended dosage is 600 mg twice a day, to be taken with meals. If gastrointestinal intolerance develops, the dosage should be halved and again increased to full dose within 3–4 days because subtherapeutic doses increase the risk of viral resistance (Lewin et al., 1997). The drug should be taken 2 hours apart from ddI (Fact Sheet 401, 2006).
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Table 6. Checklist for drugs interacting with ritonavir (Lewin et al., 1997)
Group |
Substrate |
|
|
Analgesics, NSAIDS |
Meperidine, piroxicam, propoxyphene |
Antimicrobial agents |
Clarithromycin, sulfamethoxazole |
Anticoagulants |
Warfarin |
Antidepressants |
Bupropion |
Antihistaminics |
Astemizole, terfenadine |
Antimycobacterial drugs |
Rifampicin, rifabutin |
Antiretroviral drugs |
Zidovudine, saquinavir |
Barbiturates |
Phenobarbital |
Bronchodilators |
Theophylline |
Calcium blockers |
Heptidil |
Ergot alkaloids |
Dehydro ergotamine |
Gastrointestinal drugs |
Cisapride |
Neuroleptics |
Phenytoin, Clozapine, pimozide |
Opium derivatives |
Codeine |
Steroids |
Dexamethasone, Ethinyl estradiol |
Oral hypoglycemics |
Tolbutaminde |
Psychotropics |
Chlorpromazine, alprazolam, estazolam, midazolam, triazolam, |
|
diazepam, flurazepam, clorazepate, zolpidem |
|
|
Storage Requirements
RTV should be stored under refrigeration. But, single doses can be kept at room temperature (up to 25°C or 77°F) for 12 hours (Harries et al., 2004).
Side Effects
Toxic effects include nausea, headache, vomiting, and diarrhoea, which may decrease with time. Alteration in taste has been reported. Circumoral paresthesia (numbness and burning) is a dose-dependent side effect.
Monitoring during Therapy
Elevated levels of serum triglycerides (more than twice normal), uric acid, CPK, and hepatic enzymes may be seen. These parameters should be monitored and RTV should be stopped if hepatic enzyme levels are more than three times normal (Lewin et al., 1997).
[D] LOPINAVIR/RITONAVIR (LPV/R)
This combination is indicated in patients who are older than 6 months. LPV/r combination is available as oral solution (80 mg per mL LPV + 20 mg per mL RTV) and as capsules (133.3 mg LPV + 33.3 mg RTV). The oral solution has bitter taste. (Harries et al., 2004). Liquid preparations are to be taken with food while there are no food restrictions when capsules are used (Fact Sheet 401, 2006).
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Dosage
For patients aged more than 6 months to 13 years: Surface area-based dosing – 225 mg per m2 LPV + 57.5 mg per m2 RTV twice daily. Weight-based dosing: 7–15 kg – 12 mg per kg LPV + 3 mg per kg RTV twice daily; 15–40 kg – 10 mg per kg LPV + 2–5 mg per kg RTV twice daily. The maximum dose for patients weighing more than 40 kg is 400 mg LPV + 100 mg RTV (three capsules or 5 mL oral solution) twice daily. Though the oral solution and capsules can be stored at room temperature (up to 25°C or 77°F) for 2 months, they should be preferably stored under refrigeration (Harries et al., 2004).
[E] SAQUINAVIR (SQV)
Pharmacology
SQV is indicated in HIV-infected patients older than 12 years of age. Low absorption may increase the risk of HIV-resistance to PIs. However, bioavailability is improved when SQV is taken with grapefruit juice or with RTV. Serum half-life is 1–2 hours. SQV is metabolised in the liver by cytochrome P450 isoenzyme 3A4. Low bioavailability (about 4 per cent) on oral administration is due to incomplete absorption and extensive first-pass metabolism (Lewin et al., 1997).
Additive or synergistic effects are seen when dual or triple combinations (with RTIs) are employed. Cross-resistance is not seen with RTIs but 20 per cent of SQV-resistant strains exhibit cross-resistance with other PIs. When combined with ZDV and ddC, saquinavir is highly effective in suppressing the viral load and in increasing CD4 cell counts, even in patients with relatively advanced disease (Collier et al., 1996). Saquinavir is available as 200 mg capsules. The recommended dosage is 600 mg twice a day, taken orally with, or within 2 hours of a high-fat meal (Lewin et al., 1997).
Drug Interactions
Drugs that induce hepatic enzymes (rifampicin, rifabutin, phenytoin, carbamazepine) further decrease bioavailability of saquinavir and should not be co-administered with saquinavir. Like other PIs, it interacts with many drugs. Rifampicin and rifabutin reduce the plasma levels of saquinavir by 80 and 40 per cent, respectively. Drugs that decrease levels of saquinavir, thus causing its therapeutic failure include rifabutin, rifampicin, carbamazepine, NVP, phenobarbital, and terfenadine. Saquinavir increases the blood levels of the following drugs, causing their toxicity if co-administered – alprazolam, astemizole, cimetidine, cisapride, clarithromycin, clindamycin, cyclosporin A, diazepam, felodepine, itraconazole, ketoconazole, lovastatin, midazolam, nifedipine, simvastatin, terfenadine, triazolam, and tricyclic antidepressants (Lewin et al., 1997). The herb St. John’s Wort lowers the blood levels of some PIs and therefore should not be co-administered (Fact Sheet 449, 2006).
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Side Effects
Triple therapy does not increase toxic effects (Fischl et al., 1987). Toxic effects include gastrointestinal intolerance, abdominal discomfort, nausea, diarrhoea, oral ulceration, skin rash, headache, and elevated transaminases. It should be used cautiously in patients with hepatic impairment (Lewin et al., 1997).
[F] OTHER PROTEASE INHIBITORS
TIPRANAVIR (Aptivus, PNU 140690) – This drug was approved by the US FDA in 2005 (Fact Sheet 449, 2006). Tipranavir boosted with RTV should not be used as part of an initial ARV regimen. The adult dose comprises two tablets (gel capsules) of 250 mg with one 100 mg tablet of RTV, to be taken with food, particularly high-fat meals, twice daily. The drug should be stored under refrigeration until the bottle is opened. After opening the bottle, the gel capsules may be stored for up to 60 days at room temperature. Its side effects include nausea, vomiting, diarrhoea, abdominal pain, fatigue, skin rash, headache, and aggravation of impaired liver function. Patients with hepatitis B or C should get their liver functions monitored periodically. Women taking oral contraceptives may get a skin rash and the efficacy of contraception may be reduced. The combination of tipranavir and RTV can cause increases in blood levels of cholesterol and triglycerides. The drug is best avoided in persons with bleeding disorders because few cases of internal bleeding were reported in 2006, some of them fatal. Tipranavir being a sulfa drug, history of sulfa allergy should be elicited before prescribing the drug. It interacts with multiple drugs (see under darunavir, below), lowers the blood levels of methadone, and causes excessive sedation if buprenorphine is co-administered (Fact Sheet 449, 2006).
Amprenavir (APV) – The drug may be used in combination with RTV. The adult dose of APV is eight tablets of 150 mg twice daily, to be taken with or without food. High-fat foods are to be avoided. The drug should not be taken within 1 hour of antacids. The reported side effects are nausea, vomiting, diarrhea, skin rash, circumoral paresthesia, and abdominal pain (Fact Sheet 401, 2006).
Atazanavir (ATV) – The adult dose is 200 mg once daily for patients new to ARV treatment or 150 mg with 100 mg of RTV once a day, to be taken with food. The adverse effects are bilirubinemia, nausea, vomiting, diarrhea, headache, skin rash, abdominal pain, tingling in hands or feet, depression, and cardiac arrhythmias (Fact Sheet 401, 2006).
Darunavir (TMC 114, Preztisa) – This drug was approved by the FDA (USA) in June 2006 (Fact Sheet 440, 2006) for use in HIV-infected persons who have already used other ARV drugs (Fact Sheet 450, 2006). The adult dose is 600 mg (two tablets of darunavir) along with 100 mg (one tablet) RTV, twice daily,