Category Archives: 35. Drug Profiles

Drug Profiles

– Christian Hoffmann –

3TC (lamivudine)

Manufacturer: ViiV Healthcare.

Indication and trade names: as component of a combination ART for both naïve and pretreated HIV-infected patients. Of note, the lower dosage of 3TC which is approved for Hepatitis B is not recommended in HIV patients. 3TC is a component of the following:

  • Epivir® tablets, 150 mg or 300 mg 3TC.
  • Epivir® oral solution, 10 mg per ml 3TC.
  • Combivir® film-coated tablets, 150 mg 3TC+300 mg AZT.
  • Trizivir® film-coated tablets, 150 mg 3TC+300 mg AZT+300 mg ABC.
  • Kivexa® (USA: Epzicom®) film-coated tablets, 300 mg 3TC+600 mg ABC.
  • Zeffix® film-coated tablets, 100 mg 3TC. Caution: Only for HBV, never for HIV!
  • Zeffix® oral solution, 5 mg per ml. Only for HBV, never for HIV (lower dosage)!

Standard dose: 300 mg QD or 150 mg BID. Children receive 4 mg/kg with a maximum of 150 mg BID. Dose adjustment is required with reduced creatinine clearance. For patients with creatinine clearance of between 30-49 ml/min, a dose of 150 mg QD is recommended. Below 30, only the oral solution should be used.

Creatinine Clearance (ml/min)

Initial Dose

Maintenance dosage

>50, 30-49

150 mg (15 ml)

150 mg (15 ml) QD

15–29

150 mg (15 ml)

100 mg (10 ml) QD

5–14

150 mg (15 ml)

50 mg (5 ml) QD

<5

50 mg (5 ml)

25 mg (2.5 ml) QD

Side effects: mild and uncommon. Fatigue, nausea, vomiting, diarrhea, headache, insomnia and myalgia may occur, but are usually due to the other drugs in the combination (see AZT and ABC). Polyneuropathy, pancreatitis, anemia and lactic acidosis are rare.

Comments: Usually well-tolerated, 3TC remains an often-prescribed NRTI, even fourteen years after the date of its first registration in 1996. 3TC is available in different dosages and several fixed dose combination drugs. Resistance to 3TC develops quickly but enhances the viral susceptibility to AZT and impairs viral fitness. 3TC is also effective against hepatitis B (attention: development of HIV resistance can be quite fast when used as an HBV monotherapy. In addition, there is a risk of HBV rebound upon 3TC discontinuation in an ART regimen). The dose required for HBV treatment is lower than that approved for HIV and should never be used in HIV infected patients.

Abacavir (ABC)

Manufacturer: ViiV Healthcare.

Indications and trade name: as component of a combination ART for both naïve and pretreated HIV patients. Abacavir is a component of the following:

  • Ziagen®  film-coated tablets, 300 mg ABC.
  • Ziagen® oral solution, 20 mg per ml.
  • Kivexa® (USA: Epzicom®) film-coated tablets, 600 mg ABC+300 mg 3TC.
  • Trizivir® film-coated tablets, 300 mg ABC+150 mg 3TC+300 mg AZT.

Standard dose: 300 mg BID or 600 mg QD, with or without food. Although mainly metabolized by the liver, abacavir should be avoided in patients with severe renal insufficiency (GFR <20 ml).

Side effects: abacavir causes a hypersensitivity syndrome (HSR) in about 3 to 8% of patients. HSR usually occurs within the first six weeks after initiation of treatment. Pruritus and rash are common, but may also be absent. HSR may present as just fever and slowly developing malaise. Gastrointestinal complaints (nausea, diarrhea, abdominal pain) and fatigue are also possible, but not necessarily linked to the HSR. Elevated liver function tests, insomnia, dizziness, breathlessness, sore throat or cough are rare. Before starting abacavir, a test for the HLA-B*5701 allele is strongly recommended. HLA testing reduces the HSR risk considerably, but not completely. Rechallenge after suspected HSR may be fatal and is contraindicated. It is also contraindicated after treatment interruption if HSR cannot be definitively ruled out in retrospect. Since 2008, cohort studies have reported an elevated risk of myocardial infarction in patients with recent use of abacavir. The mechanism for this is not clear. Although newer studies did not confirm these findings, some experts still say that it seems prudent to withhold abacavir from patients with high underlying cardiovascular disease risk if suitable alternative regimens are available.

Comments: Abacavir is an NRTI (guanosine analog) with good CNS penetration. It is usually well-tolerated and has little mitochondrial toxicity. The main problem with abacavir is a hypersensitivity reaction (HSR) which can be avoided by prior HLA testing.

Acyclovir

Manufacturer and trade names: diverse manufacturers, therefore several trade names such as Aciclobeta®, Aciclostad®, Aciclovir®, Zovirax®.

Indications: herpes zoster, as well as prophylaxis of serious herpes simplex infections in immunosuppressed adults.

Dose: for dermatomal herpes zoster 800 mg orally five times a day for one week. In cases of disseminated or complicated herpes zoster, 10 mg/kg IV TID. Reduce dosage in having patients with renal insufficiency at a creatinine clearance of 25-10 ml/min, 800 mg TID, and at <10 ml/min, 800 mg BID.

For genital HSV infection, 400 mg five times a day. In severe cases (ulcerating genital herpes) intravenous treatment with 5-10 mg/kg IV TID. For HSV encephalitis or HSV esophagitis 10 mg/kg IV TID.

Side effects: uncommon. Headache, nausea and elevation of creatinine may occur. Phlebitis can occur with intravenous dosing.

Comments: approved and well tolerated HZV/HSV medicine. Generics are sometimes significantly cheaper than the originally introduced formulation, Zovirax®. Initiation of treatment for HSV infections should be within the first 24 hours after appearance of symptoms and when possible, for HZV infection within the first 4 days. Adequate fluid intake is important. Newer studies reported on a moderate but significant effect on HIV replication.

Agenerase®, see Amprenavir.

Ambisome®, see Amphotericin B.

Amphotericin B

Manufacturer: Bristol-Myers Squibb (Amphotericin B®), Gilead (Ambisome®), Dermapharm (Ampho-Moronal®).

Indications and trade names: diverse. Amphotericin B® is indicated for organ mycoses and generalized mycoses, primarily candidiasis, aspergillosis, cryptococcosis and histoplasmosis. AmBisome® (more as twice as expensive) is indicated only if conventional Amphotericin B® is contraindicated due to kidney dysfunction or intolerance. The indication also applies to visceral leishmaniasis. Suspension and tablets are only licensed for oral candidiasis. Amphotericin is a component of the following:

  • Amphotericin B® injection vial, 50 mg of powder.
  • AmBisome® injection vial, 50 mg of dry agent.
  • Ampho-Moronal® suspension, 100 mg/ml.
  • Ampho-Moronal® lozenges, to 10 mg.

Dosage (per day): when using Amphotericin B®, always apply test dose first (see below). For aspergillosis 1.0-1.5 mg/kg, for other mycoses 0.5-1 mg/kg usually suffices. Maximum dose is 1.5 mg/kg. In case of over-dosage, respiratory and cardiac arrest can occur. Dose of Ambisome®: initial 1 mg/kg QD, if necessary may be gradually increased to 3 mg/kg.

Side effects: nephrotoxicity, hypokalemia and gastrointestinal complaints. Frequent: fever, chills, and hypotension approximately 10-20 min after starting infusions. Thrombophlebitis (non-liposomal amphotericin B only via a central venous line). Side effects are generally less severe with Ambisome®.

Comments: daily monitoring of electrolytes, creatinine, BUN, ALT, blood count.   A central venous line is always necessary due to hypokalemia and the usually required potassium substitution. Sodium should be kept at normal levels. Do not combine with other nephrotoxic drugs.

Always prehydrate with 1000 ml 0.9% NaCl. Always first test dose with 5 mg in 250 ml 5% glucose over 30–60 min with strict monitoring of blood pressure and pulse for the first hour. If the test dose is tolerated, then half of the planned maintenance dose may subsequently be given on the same day. In cases of fever or chills (can be very impressive), the following may be repeated after 30 min: 50 mg pethidine (e.g., Dolantin®) IV plus 1 ampule clemastine (e.g., Tavegil®), steroids only if complaints persist (prednisolone 1 mg/kg).

If side effects are severe, then switch to Ambisome®, which is probably not more effective than conventional amphotericin B but significantly better tolerated and less nephrotoxic (no test dose, no prehydration, no central line necessary). Never mix amphotericin infusions, and always protect from light. Infuse slowly. The longer the infusion time (>3 hours), the better the tolerability. Always use 5% glucose as a diluting agent.

Amprenavir (Agenerase®), replaced by fosamprenavir in 2008. See below.

Atazanavir

Manufacturer: Bristol-Myers Squibb.

Indications and trade name: Indicated for treatment of HIV-infected adults as part of a combination. Since 2008, it has been used for both pretreated and ART-naïve patients. Atazanavir is a component of the following:

  • Reyataz® capsules, 150 mg, 200 mg, 300 mg.

Dosage: 300 mg atazanavir QD combined with 100 mg ritonavir. If ritonavir is not tolerated, atazanavir can be given 400 mg OD, without booster (combination with tenofovir should then be avoided). If atazanavir is combined with efavirenz (even if boosted), increase dosage to 400 mg. The capsules should be swallowed (not chewed) and taken with a meal.

Side effects: very often hyperbilirubinemia (up to 50%), also with jaundice; rarer elevated transaminases. Diarrhea, nausea, vomiting, headache, insomnia and abdominal pain are also relatively rare. In contrast to other PIs, there is less dyslipidemia. The effect on lipodystrophy remains unknown. Rarely nephrolithiasis.

Interactions, warnings: Do not combine with indinavir. Caution with impaired liver function. Atazanavir is contraindicated in patients with Child-Pugh B and C.

Be careful with proton pump inhibitors (PPI) and antacids.

Combinations with the following pharmaceuticals are contraindicated: cisapride, midazolam, triazolam, simvastatin, lovastatin, ergotamines, calcium antagonists. Life-threatening interactions may occur with concomitant administration of amiodarone, lidocaine (systemic dosing), tricyclic anti-depressants and quinidine (measure plasma levels). Do not combine boosted atazanavir with clarithromycin.

It should not be given with rifampin (reduces plasma levels of atazanavir by 90%). Reduce the rifabutin dose by 75% (instead of 300 mg daily, give only 150 mg every other day or three times per week).

Comments: Well-tolerated PI with a favorable lipid profile and a low pill burden which can be taken once daily. Should be boosted with ritonavir. The most important side effect is hyperbilirubinemia, which often presents as jaundice. There are some relevant interactions – primarily with proton pump inhibitors and antacids, but also with tenofovir, efavirenz, and ddI.

Atovaquone

Manufacturer: GlaxoSmithKline.

Indications and trade name: Acute treatment of mild or moderate PCP in cases of hypersensitivity to cotrimoxazole; in combination with proguanil for the treatment and prophylaxis of malaria. Off-label, can be used as PCP prophylaxis (as reserve) and as acute treatment of cerebral toxoplasmosis.

Atovaquone is a component of the following:

  • Wellvone® suspension, 750 mg atovaquone/5 ml.
  • Malarone® film-coated tablets, 250 mg atovaquone and 100 mg proguanil.

Dose: as therapy for acute PCP (or toxoplasmosis): 750-1500 mg BID (i.e., 1-2 measuring spoons of 5 ml BID) for 21 days. For prophylaxis 750 mg BID (i.e., 1 measuring spoon of 5 ml BID) or 1500 mg QD.

Side effects: gastrointestinal complaints such as nausea, vomiting and diarrhea are frequent (but often mild), as are rashes, which occur in approximately 20% of patients. Less common are headache and insomnia. Elevated liver enzymes, amylase. Anemia, leukopenia (rare).

Comments: Atovaquone should be taken with meals, ideally with fatty dishes, as this improves absorption. Rifampin and possibly also rifabutin lower plasma levels of atovaquone by approximately 50%. Fluconazole probably increases levels.

Nowadays, used only rarely. Atovaquone is considerably more expensive than other drugs for PCP prophylaxis.

Atripla®

Manufacturer: co-produced by Gilead Sciences, Bristol-Myers Squibb and MSD.

Indications and trade name: adult HIV-infected patients. It should be noted that in Europe, approval for Atripla® is more strict than in the US. The E(M)EA has only approved the use of Atripla® in patients who have already achieved virologic suppression to below 50 copies/ml on their current antiretroviral regimen for at least three months. Furthermore, patients must not have experienced virologic failure with an earlier treatment combination or be known to have resistance to any of the drugs in Atripla®.

  • Atripla® film-coated tablets with 600 mg EFV, 200 mg FTC, 300 mg TDF.

Dose: one tablet daily in the evening, unchewed, on an empty stomach.

Comments: the first complete ART in one single tablet per day; a convenient simplification. In Europe, the above-mentioned limitation of the indication applies. For side effects, see sections on tenofovir (caution with renal function), efavirenz (CNS side effects) and FTC.

Azithromycin

Manufacturer and trade names: diverse, therefore several trade names, such as Azithromycin®, Zithromax®, Ultreon®.

Indications: treatment and prophylaxis of MAC infection. Infections of the upper and lower respiratory tract, otitis media. Uncomplicated gonorrhea, uncomplicated genital infections with Chlamydia trachomatis, chancroid. Azithromycin is a component of the following:

  • Ultreon® film-coated tablets, 600 mg.
  • Zithromax® film-coated tablets, 250 mg and 500 mg.
  • Zithromax®, dry suspension, 200 mg per 5 ml.

Dose: primary prophylaxis of disseminated MAC infection: 1200 mg azithromycin once weekly (2 tablets Ultreon® 600 mg per week). MAC treatment: 1 tablet Ultreon® 600 mg QD, only in combination with ethambutol and rifabutin.

Infections of the respiratory tract: 500 mg QD for 3 days.

Uncomplicated gonorrhea, uncomplicated genital infections or chancroid with Chlamydia trachomatis: 1000 mg azithromycin may be given as a single dose.

Side effects: mainly gastrointestinal with stomach cramps, nausea, vomiting, and diarrhea. Rarely, elevations of transaminases, cholestatic jaundice. Reversible ototoxicity with high doses. Rarely, taste disturbances, discoloration of the tongue. Allergies.

Comments: This macrolide antibiotic has a long half-life and good tissue penetration. In patients with genital infections, a single dose is sufficient. For respiratory tract infections, azithromycin should be given for 3-5 days. In HIV infection, azithromycin has been often used as (permanent) prophylaxis or treatment of MAC infections.

AZT (zidovudine)

Manufacturer: ViiV Healthcare.

Indications and trade name: as component in a combination ART for both naïve or pretreated HIV patients. Prevention of maternal-fetal HIV transmission. AZT is a component of the following:

  • Retrovir® hard capsule, 100 mg AZT and 250 mg AZT.
  • Retrovir® film-coated tablets, 300 mg AZT.
  • Retrovir® oral solution, 100 mg AZT per 10 ml.
  • Retrovir® concentrate, 10 mg AZT per ml (5 injection vials 200 mg each).
  • Combivir® film-coated tablets, 300 mg AZT+300 mg 3TC.
  • Trizivir® film-coated tablets, 300 mg AZT+150 mg 3TC+300 mg abacavir.

Dose: 250 mg BID (in Combivir®and Trizivir® 300 mg BID). In patients with serious renal impairment (creatinine clearance below 20 ml/min, hemodialysis) 300 mg daily. With severe hepatic impairment 100 mg TID.

Side effects: nausea, vomiting, abdominal discomfort, headache, myalgia, and dizziness. Macrocytic anemia (MCV almost always elevated), rarely neutropenia. Elevations in LDH, CPK and transaminases may occur. Episodes of lactic acidosis are rare.

Interactions, warnings: do not combine with d4T. There is increased myelotoxicity if used with other myelosuppressive drugs, especially gancyclovir but also co-trimoxazole, dapsone, pyrimethamine, interferon, sulfadiazine, amphotericin B, ribavirin and various other chemotherapeutic agents. Ribavirin antagonizes the antiviral activity of AZT in vitro (combination should be avoided).

Initially monthly monitoring of blood count, transaminases, CPK and bilirubin. Gastrointestinal complaints can be treated symptomatically and usually subside after a few weeks. Anemia can develop even after months.

AZT should always be a component of transmission prophylaxis.

Comments: The first NRTI (thymidine analog) on the market and the oldest HIV drug of all (registered in 1987). Still partner in some ART therapies. However, due to numerous toxicities (myelotoxicity, mitochondrial toxicity) AZT is prescribed considerably less frequent than previously. Remains important in transmission prophylaxis. Comprehensive data, good penetration of the blood-brain barrier. Generics to be expected.

Boceprevir

Manufacturer: MSD.

Indications and trade name: Patients with chronic hepatitis C, genotype 1. Boceprevir should only be used in combination with peginterferon alfa and ribavirin, usually after a lead-in phase of four weeks with these two drugs. Treatment duration (24-44 weeks) depends on treatment response, previous HCV therapy and on preexistent cirrhosis.

  • Victrelis® hard capsules, 200 mg.

Dose: 800 mg administered orally three times daily (four capsules every 7-9 hours) with food (a meal or light snack). A dose reduction is not recommended. In patients with renal impairment, no dose adjustment is required.

Side effects: Nausea, fatigue, headache, dysgeusia (alteration of taste). In particular, anemia and neutropenia seem to become more frequent and severe when boceprevir is added to peginterferon and ribavirin.

Interactions, warnings: do not use in other HCV genotypes than genotype 1. Boceprevir is a strong CYP3A inhibitor, and numerous interactions must be considered prior to and during therapy. Dose adjustments are expected to be necessary when co-administered with NNRTIs and PIs (studies forthcoming). Do not combine with carbamazepine, rifampin, cisapride, lovastatin, simvastatin, triazolam.

Comments: New HCV drug which was approved by the FDA in May 2011. In Europe, the first HCV-PI on the market (approval July 2011). However, due to numerous toxicities of the triple HCV therapy, the use of boceprevir is only recommended in experienced centers. The safety and efficacy have not yet been established in HIV infected patients.

Caelyx®, see Doxorubicin, liposomal.

Cidofovir

Manufacturer: Gilead Sciences.

Indications and trade name: CMV retinitis in HIV-infected patients without renal dysfunction, mainly in cases of resistance/contraindications to gancyclovir or foscavir. Some experts use cidofovir for PML (off-label use), although efficacy is uncertain. Cidofovir is a component of the following:

  • Vistide® injection vial, 375 mg per 5 ml (= 75 mg/ml).

Dose: induction dose 5 mg/kg IV weekly, by day 21 maintenance therapy with 5 mg/kg IV every two weeks. A precise treatment plan (see below) is necessary.

Side effects: renal failure, which can occur even after 1 dose of cidofovir. Less frequent: neutropenia, dyspnea, alopecia, decreased intraocular pressure, iritis, uveitis.

Fever, chills, headache, rash, nausea and vomiting are usually caused by probenecid and should subside within 12 hours. Complaints may be lessened with food intake, antipyretics, or antiemetics.

Warnings: renal function (serum creatinine, electrolytes, proteinuria) should be checked before each dose of cidofovir. If serum creatinine increases by more than 0.3 mg/dl, reduce dose to 3 mg/kg. If serum creatinine increases by more than 0.5 mg/dl above levels prior to treatment, discontinue cidofovir. Cidofovir is always contraindicated at serum creatinine levels >1.5 mg/dl or creatinine clearance below 55 ml/min or proteinuria >100 mg/dl. Always ensure sufficient hydration. Cidofovir should be given according to the following scheme:

–3 h 2 g probenecid (4 tablets of 500 mg), prior poss. 20 drops metamizole plus 50 mg prednisolone
–3 to –1 h 1000-2000 ml 0.9% NaCl
0 to + 2 h Cidofovir in 500 ml 0.9% NaCl over 1-2 h. Concurrently 1000 ml 0.9% NaCl.
+4 h 1 g probenecid (2 tablets of 500 mg), prior poss. 20 drops metamizole
+10 h 1 g probenecid (2 tablets of 500 mg), prior poss. 20 drops metamizole

Potentially, nephrotoxic drugs such as aminoglycosides, amphotericin B, foscarnet, IV pentamidine or vancomycin must be avoided or discontinued at least 7 days prior to treatment with cidofovir. Probenecid is necessary to reduce nephrotoxicity. Probenecid has drug interactions with acetaminophen, acyclovir, angiotensin converting enzyme inhibitors, aminosalicylic acid, barbiturates, benzodiazepines, bumetanide, clofibrate, methotrexate, famotidine, furosemide and theophylline.

Comments: Reserve drug in severe CMV infections. Rarely used due to considerable nephrotoxicity. The effect in PML is more than questionable.

Clarithromycin

Manufacturer and trade names: diverse manufacturers, therefore several trade names, such as Clarithromycin-CT®, Klacid®, Mavid®.

Indications: prophylaxis and treatment of MAC disease. Infections of the respiratory tract, ENT area and the skin. Clarithromycin is a component of the following (selection):

  • Mavid® film-coated tablets, 500 mg.
  • Klacid® film-coated tablets, 250 mg.

Dose: with MAC 500 mg BID, both for primary prophylaxis and for maintenance therapy. 50% dose reduction if creatinine clearance is below 30 ml/min. At respiratory tract infections 250 mg BID will suffice.

Side effects: mainly gastrointestinal complaints such as nausea, vomiting, abdominal discomfort and diarrhea; in addition, allergic skin reactions, headache, elevated transaminases, alkaline phosphates and bilirubin.

Interactions, warnings: no concurrent treatment with rifampin, carbamazepine, cisapride, terfenadine, pimozide and other macrolide antibiotics such as erythromycin or azithromycin. Lopinavir and ritonavir increase clarithromycin levels. If administered concurrently, oral treatments with clarithromycin and AZT should be taken 1-2 hours apart.

Comments: Macrolide antibiotic with a shorter half-life than azithromycin. The daily dose should not exceed 500 mg BID.

Clindamycin

Manufacturer and trade name: diverse manufacturers, therefore several trade names, such as Aclinda®, Clindabeta®, Clindamycin-ratiopharm®, Sobelin®.

Indications: for HIV+ patients, mainly cerebral toxoplasmosis. Also for serious infections by anaerobes, staphylococci (because of good tissue and bone penetration also used in dentistry).

Dose: 600 mg IV QD or 600 mg oral QD (always with pyrimethamine and leucovorin). Half dose for (oral) maintenance therapy. In renal failure, reduce dose to a quarter or a third of the normal dose.

Side effects: diarrhea in 10-30% of patients. Allergies are also frequent and often require discontinuation. In cases of infection with Clostridium difficile “Pseudomembranous colitis”, the clinical spectrum ranges from mild watery stool to severe diarrhea with blood and mucous, leukocytosis, fever and severe abdominal cramps which may progress to peritonitis, shock and toxic megacolon.

Warnings: Clindamycin is contraindicated in inflammatory bowel disease and antibiotic-induced colitis. Caution with reduced hepatic or renal function and in asthma. No concurrent administration of antiperistaltics. For every occurrence of diarrhea on clindamycin, discontinue and give vancomycin.

Comments: Still used in patients with cerebral toxoplasmosis. Several side effects, caution with colitis.

Combivir®

Manufacturer: ViiV Healthcare.

Indications and trade name: as a component in combined therapy for ART naïve or pretreated HIV patients.

  • Combivir® film-coated tablets, 300 mg AZT+300 mg 3TC.

Dose: 1 tablet BID. In cases of reduced renal function (creatinine clearance below 50 ml/min) and anemia, Combivir® should be replaced with the individual drugs to allow for adjustment of 3TC and AZT doses.

Comments: the first fixed-dose combination in HIV medicine (1998). For a long time one of the most used drugs. While it is prescribed less, it remains an alternative in certain circumstances. See AZT for side effects.

 Complera®

Manufacturer: Gilead Sciences and Janssen-Cilag.

Indications and trade name: For ART naïve or pretreated HIV patients.

  • Complera® film-coated tablets with 25 mg RPV, 200 mg FTC, 300 mg TDF.

Dose: 1 tablet per day. Should be taken with a meal. In cases of reduced renal function (creatinine clearance below 50 mL/min), Complera® should be avoided.

Side effects: For side effects, see sections on tenofovir (caution with renal function, Fanconi syndrome), rilpivirine and FTC.

Interactions, warnings: For interactions, see also sections on tenofovir, rilpivirine and FTC. Complera® should not be coadministered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase: carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, proton pump inhibitors (PPIs), St. John’s wort (Hypericum perforatum). In patients with HIV-1 RNA greater than 100,000 copies/mL, the observed virologic failure rate conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to Atripla®.

Comments: The second complete ART (fixed dose combination, FDC) in one single tablet per day, approved by the FDA in August 2011. In Europe, approval is still pending. In highly viremic patients, resistance rates with this well-tolerated FDC are higher than seen with Atripla®. As increase in gastric PH decreases rilpivirine plasma concentrations, caution is needed with antacids and PPIs.

Co-trimoxazole (Trimethoprim-sulfamethoxazole)

Manufacturer and trade names: diverse manufacturers, therefore several trade names, such as Cotrimratiopharm®, Cotrimstada®, Eusaprim®.

Indications: Prophylaxis and treatment of Pneumocystis pneumonia (PCP). Prophylaxis and treatment (reserve drug) of cerebral toxoplasmosis. Also for other infections, for example urinary tract infections.

  • Cotrim 960®  tablets, 160/800 mg TMP/SMX.
  • Cotrim forte® tablets, 160/800 mg TMP/SMX.
  • Cotrim 480® tablets, 80/400 mg TMP/SMX.
  • Bactrim® liquid suspension, adults (16/80 mg/ml), children (8/40 mg/ml).
  • Bactrim® ampule, 80/400 mg TMP/SMX.

Dose: As PCP prophylaxis: 80/400 mg QD or 160/800 mg TMP/SMX 3 x/week. As PCP therapy: 5 mg/kg (based on TMP) orally or IV q 8 h x 21 days, therefore usually 5 to 6 ampules each 80/400 mg TID.

Toxoplasmosis prophylaxis: 1 tablet (160/800 mg) QD. With reduced renal function, use half-dose with creatinine clearance of 15 to 50 ml/min. Co-trimoxazole is contraindicated below 15 ml/min.

Side effects: allergies. High intravenous doses also cause myelotoxicity (anemia, neutropenia), nausea, vomiting, headache, raised transaminases. Treatment can often be continued in cases of mild allergy.

Comments: caution with sulfonamide allergy. Co-trimoxazole oral suspension for children can be used for desensitization. Increase the dose slowly over six days from 12.5, 25, 37.5, 50 and 75 to 100% of the 480 mg tablet dose. Co-trimoxazole can increase levels of anticoagulants and phenytoin and reduce the efficacy of oral contraceptives.

Crixivan®, see Indinavir.

Cymeven®, see Gancyclovir.

d4T (stavudine)

Manufacturer: Bristol-Myers Squibb.

Indications and trade name: HIV infection.

  • Zerit® hard capsule, 20, 30 and 40 mg.
  • Zerit® powder for preparation of an oral solution, 1 mg/ml.

Dose: 40 mg BID for body weight >60 kg, 30 mg BID for body weight <60 kg. On empty stomach or with a light meal. In renal failure:

Weight CrCl 26-50 ml/min CrCl below 26 ml/min (incl. dialysis patients)*
<60 kg 15 mg BID 15 mg QD
>60 kg 20 mg BID 20 mg QD
*Hemodialysis patients should take d4T after dialysis, and at the same time on the other days.

Side effects: more than other NRTIs, mitochondrially toxic, lipoatrophy. Peripheral neuropathy, especially in combination with ddI (up to 24%). The following are less frequent: diarrhea, nausea, headache, hepatic steatosis and pancreatitis. Very rare, but potentially fatal are lactic acidosis, which occurs mostly in combination with ddI (especially in pregnancy).

Comments: This thymidine analog was long-considered an important alternative to AZT. Due to the mitochondrial toxicity (lipoatrophy, lactic acidosis, peripheral neuropathy), the use of d4T is no longer recommended.

Dapsone

Manufacturer: Fatol.

Indications: reserve drug for prophylaxis of PCP and cerebral toxoplasmosis. Other (rare) areas of application are in dermatology (bullous pemphigoid), rheumatology and leprosy.

  • Dapson-Fatol® tablets, 50 mg.

Dose: 100 mg daily. Alternative: 50 mg QD + pyrimethamine 50 mg/week + folinic acid 30 mg/week.

Side effects: allergies (pruritus, rash), fever. Frequently hemolytic anemia (with almost obligatory elevation of LDH), hepatitis.

Comments: dapsone is contraindicated in severe anemia and must be used with caution in G-6-PD deficiency. It is contraindicated in Mediterranean G-6-PD deficiency. Not to be taken simultaneously with ddI, antacids and H2 blockers (to be taken at least two hours apart). Rifabutin and rifampin lower dapsone levels.

Daraprim®, see Pyrimethamine.

Darunavir 

Manufacturer: Janssen-Cilag.

Indications and trade name: to be used in either ART-naïve or pretreated HIV patients.

  • Prezista® tablets, 400 and 600 mg.
  • Prezista® tablets, 75 and 150 mg (pediatric formulation).

Dose: Depending on antiretroviral pretreatment, once or twice daily:

ART-naïve:  800 mg QD (2 tablets of 400 mg) + 100 mg ritonavir QD

Pretreated:    600 mg BID (1 tablet of 600 mg) + 100 mg ritonavir BID

In 2009, darunavir was also approved for children aged 6 years and older. Recommended dosage is 375/50 mg BID (Wt ≥20 kg to <30 kg), 450/60 BID (Wt ≥30 kg to <40 kg). At ≥40 kg, adult dosage is recommended. OD regimens with darunavir should not be used in children.

Side effects: the usual PI side effects, with (moderate) gastrointestinal complaints and dyslipidemia. The dyslipidemia may not be as pronounced as with other PIs. Data on lipodystrophy is lacking. Rash (7%) within the first 2 weeks.

Interactions, warnings: darunavir should be taken with or shortly after meals. Caution for sulfonamide allergy. Since darunavir is metabolized by the cytochrome P450 system, some interactions have to be taken into account. Lopinavir and saquinavir lower the plasma levels of darunavir so should be avoided in combination. Also do not combine with St. John’s wort, astemizole, terfenadine, cisapride, pimozide, midazolam, triazolam, ergotamine derivatives, rifampicin, phenobarbital, phenytoin, and carbamazepin. Use atorvastatin instead of pravastatin at the lowest dose (10 mg). Dosage adjustments may be required with efavirenz (decreased darunavir levels and increased efavirenz levels), rifabutin (dose should be reduced to 150 mg every two days), calcium antagonists (increased levels), methadone (reduced levels). Interactions with contraceptives may occur. Maximum doses of PDE5 inhibitors when combined with darunavir, 10 mg Cialis® in 72 hours; 2.5 mg Levitra® in 72 hours; 25 mg Viagra® in 48 hours. For further information (azoles, cyclosporine, SSRIs and others) see product information.

Comments: Well-tolerated and broadly applicable protease inhibitor that has considerable activity against PI-resistant viruses. Needs to be boosted with ritonavir. Different dosages as well as interactions have to be taken into account.

Daunorubicin (liposomal)

Manufacturer: Gilead Sciences (Galen Limited), Fresenius

Indications and trade name: AIDS-associated Kaposi sarcoma with <200 CD4 cells/µl and severe mucocutaneous or visceral involvement.

  • DaunoXome® injection vial, 50 mg (25 ml).

Dose: 40 mg/m2 in 250 ml 5% glucose solution intravenously over 30-60 minutes. Repeat after 2-3 weeks.

Side effects: during infusion: back pain, flushing (up to 14 %). Symptoms usually occur during the first minutes and resolve when the infusion is slowed or stopped. Fatigue, headaches, chills. Myelosuppression, cardiomyopathy.

Interactions, warnings: liposomal doxorubicin is contraindicated in decompensated cardiomyopathy, severe myelosuppression (neutrophils <1,000/µl, platelets <50,000/µl). Cardiological examination is important (ECG, echocardiography: left ventricular ejection fraction, LVEF) before initiation of treatment and at periodic intervals during treatment.

Comments: Compared to pegylated liposomal doxorubicin, treatment with liposomal daunoribicin yields to slightly lower remission rates of KS. However, as capacity constraints for Caelyx® are expected for the remainder of 2011, DaunoXome® represents an important alternative for KS treatment.

ddC (zalcitabine),  manufacturing and distribution was stopped in 2006.

ddI (didanosine)

Manufacturer: Bristol-Myers Squibb.

Indications and trade name: HIV infection.

  • Videx® hard capsules, 125, 200, 250 and 400 mg.
  • Videx® powder, 2 g.

Dose: 400 mg QD (body weight >60 kg) or 250 mg QD (body weight <60 kg). ddI must be taken on an empty stomach, at least 2 hours after or 1 hour before meals.

Side effects: diarrhea, nausea, headache. Pancreatitis, even after longer periods of treatment. Peripheral polyneuropathy. Rarely lactic acidosis, especially in combination with d4T and ribavirin.

Interactions, warnings: acute and chronic pancreatitis are contraindications, as well therapy with ribavirin. The following drugs should be used with caution: d4T, ethambutol, cisplatin, disulfiram, INH, vincristine, etc (peripheral neuropathy).

Concurrent dosing with tenofovir should be avoided because it increases the AUC of ddI by 44%. The ddI dose should be reduced to 250 mg. Tenofovir must be taken two hours before or one hour after ddI. Treatment with indinavir, dapsone, ketoconazole, itraconazole, or tetracyclines should be given 2 hours before or after ddI.

Initially, monthly monitoring of amylase, blood count, transaminases and bilirubin. Patients should be informed about the symptoms of pancreatitis. ddI should be discontinued if there is clinical suspicion for pancreatitis with no future rechallenge.

Comments: An early NRTI. Due to considerable toxicity (pancreatitis, polyneuropathy, mitochondrial toxicity) today only used in certain resistance situations. The dose has to be adjusted according to bodyweight. Combinations with tenofovir and d4T should be avoided.

Diflucan®, see Fluconazole.

Delavirdine

Manufacturer: ViiV Healthcare (Pfizer).

Indications and trade name: HIV infection. Not licensed in Europe.

  • Rescriptor® tablets, 100 mg and 200 mg.

Dose: 400 mg TID. The tablets can be dissolved in water.

Side effects: rash, usually occurring within the first six weeks of treatment. In uncomplicated cases, give antihistamines. Discontinue if systemic effects such as fever, conjunctivitis, and myalgia occur. Nausea, elevated transaminases.

Interactions, warnings: delavirdine is contraindicated for concurrent treatment with rifabutin, rifampin, carbamazepine, phenytoin, alprazolam, astemizole, phenobarbital, cisapride, midazolam, terfenadine and triazolam.

Delavirdine interacts with numerous drugs via reduction of CYP3A activity. It increases the AUC of some PIs (saquinavir, nelfinavir), sildenafil, dapsone, clarithromycin, quinidine and warfarin. Delavirdine levels are lowered by ddI, H2 blockers, carbamazepine, phenytoin and antacids.

Comment: delavirdine is rarely used due to high pill burden and drug interactions. This NNRTI was never approved in Europe.

Doxorubicin (liposomal)

Manufacturer: Janssen-Cilag (Johnson & Johnson).

Indications and trade name: AIDS-associated Kaposi sarcoma with <200 CD4 cells/µl and severe mucocutaneous or visceral involvement.

  • Caelyx® (or Doxil®) injection vial, 10 ml (20 mg) and  25 ml (50 mg).

Dose: 20 mg/m2 in 250 ml 5% glucose solution intravenously over 30 minutes. Repeat after 2-3 weeks.

Side effects: myelosuppression, cardiomyopathy, stomatitis (rarely severe), palmar-plantar erythrodysesthesia (PPE or hand-foot syndrome – erythematous rash which may be very painful. Treatment: cool affected areas). Be careful with extravasations (never SC or intramuscular, never give a bolus.)

Interactions, warnings: liposomal doxorubicin is contraindicated in decompensated cardiomyopathy, severe myelosuppression (neutrophils <1,000/µl, platelets <50,000/µl).

Cardiological examination is important (ECG, echocardiography: left ventricular ejection fraction, LVEF) before initiation of treatment and at periodic intervals during treatment. If the cumulative dose of 450 mg/m2 is exceeded, then an echocardiography is necessary before each further cycle. It is important to inform patients of PPE (may be induced by sweating, pressure, friction – i.e., no tight gloves, no sun, no long warm showers). Cool drinks are favorable. This drug is expensive.

In August 2011, Janssen-Cilag reported production difficulties. Intermittent capacity constraints are expected for the remainder of 2011. The company cautioned doctors not to start new patients on this drug. Of note, non-liposomal and non-pegylated forms of doxorubicin are not bioequivalent. Non-anthracycline alternatives may be considered.

Edurant®, see Rilpivirine.

Efavirenz

Manufacturer: BMS (Sustiva®); MSD (Stocrin®); Gilead/BMS/MSD (Atripla®).

Indications and trade name: HIV infection.

  • Sustiva® film-coated tablets, 600 mg, in some countries known as Stocrin®.
  • Sustiva® hard capsules, 50 mg, 200 mg.
  • Sustiva® solution for oral administration as 30 mg/ml (180 ml = 5.4 g).
  • Atripla® film-coated tablets, 600 mg efavirenz +200 mg FTC +300 mg tenofovir.

Dose: 600 mg daily preferably before going to bed on an empty stomach.

Side effects: CNS symptoms occur frequently in the first weeks. Nightmares, confusion, dizziness, depression, somnolence, impaired concentration, insomnia and depersonalization. A generally mild rash (15%) may also occur in the first weeks, and continued treatment is usually possible. Elevation of liver function tests and biliary enzymes. Dyslipidemia. Occasionally painful gynecomastia.

Interactions, warnings: contraindicated in pregnancy. Caution with women of childbearing age. Efavirenz should not be taken with fatty meals (possibly higher absorption and side effects).

Contraindicated for concurrent administration with ergotamines, astemizole, cisapride, midazolam, terfenadine and triazolam. Should not be combined with contraceptives. Dose increases may be necessary for lopinavir/r (to 3 tablets BID),  atazanavir/r (400/100mg), rifabutin (450 mg), methadone (20-30%) and maraviroc (600 mg BID if no boosted PI is given).

Comments: Efavirenz is a frequently used and very effective NNRTI. However, it has some CNS side effects. Further disadvantages as with the other members of this drug class include drug interactions, a low resistance barrier and cross-resistance.

Emtricitabine (FTC)

Manufacturer: Gilead (Emtriva® and Truvada®); Gilead+BMS+MSD (Atripla®); Gilead+Janssen-Cilag (Complera®).

Indications and trade name: HIV infection.

  • Emtriva® hard capsules, 200 mg FTC.
  • Emtriva® solution, 10 mg FTC per ml.
  • Truvada® film-coated tablets, 200 mg FTC + 300 mg tenofovir.
  • Atripla® film-coated tablets, 200 mg FTC + 300 mg tenofovir +600 mg efavirenz.
  • Complera® film-coated tablets with 25 mg RPV, 200 mg FTC, 300 mg TDF.

Dose: 200 mg QD (solution recommended dose 240 mg = 24 ml). At reduced creatinine clearance, FDCs should be avoided. FTC is adapted as follows:

Cr Cl (ml/min) Dose
30–49 200 mg every 2 days
15–29 200 mg every 3 days
Below 14 or dialysis 200 mg every 4 days


Side effects: Most commonly mild headache, nausea, diarrhea, rash. Possibly hyperpigmentation.

Comments: FTC is a well-tolerated cytidine analog comparable to 3TC. FTC has the same resistance profile but has a significantly longer half-life than 3TC. Used as a component in Truvada®, Atripla® and Complera®.  Effective against HBV.

Emtriva®, see Emtricitabine.

Enfuvirtide®, see T-20.

Epivir®, see 3TC.

Eremfat®, see Rifampicin.

Filgrastim, see G-CSF.

Ethambutol

Manufacturer: among others Riemser, Fatol.

Indications and trade names: tuberculosis, MAC infection.

  • EMB-Fatol® tablets, 100 mg.
  • EMB-Fatol® film-coated tablets, 250 mg, 400 mg and 500 mg.
  • EMB-Fatol® injection solution, 1 g in 10 ml.
  • Myambutol® film-coated tablets, 100 mg and 400 mg.
  • Myambutol® injection solution, 400 mg/4 ml and 1000 mg/10 ml.

Dose: 15 to 25 mg/kg (maximum 2 g) daily, usually 3 x 400 mg tablets QD. Ethambutol should only be given as combination therapy. Dose reduction in renal failure as follows:

Cr Cl Dose
Above 75 ml/min 25 mg/kg
     40-75 ml/min 15 mg/kg
     30-40 ml/min 15 mg/kg every second day
        <30 ml/min Measurement of serum levels required (should be within the range of minimal inhibitory concentration 2-5 µg/ml after 2-4 hours)

 

Side effects: ethambutol can lead to optical neuritis with impaired vision (decreased acuity, restricted fields, loss of red-green color discrimination). It is usually reversible if ethambutol is discontinued immediately. Other side effects: nausea, vomiting, abdominal pain, headache, dizziness, pruritus, arthralgia, elevated serum uric acid (possible acute gout attacks), abnormal liver function tests.

Interactions, warnings: ethambutol is contraindicated with pre-existing optical nerve damage.

Ophthalmologic examination before initiation of treatment and subsequently at 4-week intervals (color discrimination, field of vision, acuity). Immediate discontinuation to prevent optical atrophy if drug-related impairment of vision occurs.

Patients should be informed that impairment of vision may occur and to immediately report this to the treating physician.

Aluminum hydroxide reduces absorption of ethambutol; ethambutol should therefore be taken at least one hour before antacids.

Monitor liver values and uric acid levels at monthly intervals.

Etravirine

Manufacturer: Janssen-Cilag.

Indications and trade name: in combination with a boosted protease inhibitor and other antiretroviral agents for the treatment of HIV-1 infection in antiretroviral treatment-experienced adult patients.

  • Intelence® tablets, 100 mg

Dose: 200 mg (2 x 2 pills) BID after a meal. The tablets are soluble in water.

Side effects: Mostly mild rash, nausea is rare. With mild exanthema, which usually appears in the second week, treatment can usually be continued, immediately stopping at a serious exanthema. Rarely Stevens-Johnson syndrome. In October 2009, the company published a Dear Doctor letter, reporting on three cases of TEN.

Interactions, warnings: Etravirine is a substrate of the CYP450 enzyme system as well as an inducer of CYP3A4 and an inhibitor of CYP2C9, therefore, some interactions are to be anticipated. Etravirine reduces the serum concentrations of atazanavir, maraviroc and raltegravir and increases fosamprenavir levels. On the other hand, the etravirine levels are considerably reduced by tipranavir, efavirenz and nevirapine (moderately by darunavir, saquinavir and tenofovir). Lopinavir and delavirdine increase the levels of etravirine.

Result: Etravirine should not be combined with the following: Atazanavir, fosamprenavir, tipranavir, unboosted PIs or other NNRTIs. Avoid rifampicin, carbamazepine, phenobarbital, phenytoin and St. John’s wort as well. For further details, see product information.

Comments: Etravirine is the first second-generation NNRTI that was licensed in 2008 for pre-treated patients. It is well-tolerated and effective against NNRTI-resistant HIV strains with classic NNRTI mutations like K103N. Should be combined with a boosted PI (preferably darunavir, due to the lack of data with other PIs).

Fluconazole

Manufacturer and trade name: Pfizer and many other companies, therefore several trade names, such as Diflucan®, Fluconazole CT®/Stada, or Flucobeta®.

Indications: Candida infection, cryptococcal meningitis and some rare mycoses.

  • Fluconazole® capsules, 50 mg, 100 mg, 200 mg.
  • Fluconazole® suspension, 50 mg per 10 ml.
  • Fluconazole® IV for injections, 100, 200 and 400 mg.

Dose: for oral candidiasis, 100 mg QD orally; for candida esophagitis 200 mg QD for 7-10 days. Double the dose on the first day. An attempt with a higher dose (up to 800 mg daily) may be made if there is persistent candidiasis after 10 days.

Cryptococcal meningitis: Initially, 400-800 mg daily, combined with flucytosine and amphotericin B if possible. After completion of acute therapy – usually after 6 weeks – maintenance therapy with 200 mg fluconazole daily.

Renal insufficiency: half the dose with creatinine clearance of 10 to 50 ml/min; reduce to 25% below 10 ml/min.

Side effects: overall good tolerability, rarely gastrointestinal complaints and elevated transaminases. Reversible alopecia in approximately 10% of cases with more than 400 mg daily.

Interactions, warnings: long-term treatment may lead to development of candida-resistant strains. Fluconazole is not effective against C. krusei or aspergillus. In cases of C. glabrata infection higher doses are required (sensitivity is dose-dependent). Fluconazole levels are reduced with concurrent administration of rifabutin/rifampin. Fluconazole increases the serum levels of rifabutin, atovaquone, clarithromycin, theophylline, opiates, coumarin derivatives, benzodiazepines, cyclosporine, tacrolimus, phenytoin and anti-convulsive drugs as well as AZT.

Comments: Fluconazole is the first choice for HIV-associated candidiasis and for the secondary prophylaxis of cryptococcosis (also as component of acute therapy). The tablets have good absorption. Infusions (more expensive) are only required in cases of non-adherence, severe mucositis, and/or problems with absorption.

Fosamprenavir

Manufacturer: ViiV Healthcare.

Indications and trade name: HIV infection, for both treatment-naïve and experienced patients (for limitations, see details below). US trade name: Lexiva®.

  • Telzir® film-coated tablets, 700 mg.
  • Telzir® suspension, 50 mg/ml (225 ml bottle).

Dosage in treatment-naïve patients:

  • 700 mg BID + 100 mg ritonavir BID (2 x 2 pills, normal dose).
  • 1400 mg BID (without ritonavir, not approved in Europe).
  • 1400 mg QD + 200 mg ritonavir QD (1 x 4 pills; not approved in Europe).

Dosage in PI-experienced patients:

  • 700 mg BID + 100 mg ritonavir BID (2 x 2 pills)

Side effects: most frequently diarrhea, may be severe in some cases. Also nausea, vomiting, rash (up to 20%). Rarely Stevens-Johnson syndrome (<1%).

Interactions, warnings: Fosamprenavir can be taken on an empty stomach or with a meal. Contraindicated: cisapride, pimozide, midazolam, triazolam, ergotamines. Flecainide and propafenone are also contraindicated when fosamprenavir is boosted with ritonavir. There may be life-threatening interactions upon concurrent administration of amiodarone, lidocaine (systemic), tricyclic anti-depressants and quinidine. Do not use together with rifampin (this reduces amprenavir plasma levels by 90%), delavirdine or St. John’s wort; use cautiously with simvastatin, lovastatin, sildenafil, vardenafil.

Carbamazepine, phenobarbital, phenytoin and dexamethasone can lower plasma levels of amprenavir.

Rifabutin: dose reduction of rifabutin by at least 50%. If fosamprenavir is boosted with ritonavir, a 75% reduction of the rifabutin dose is required (instead of 300 mg daily, only 150 mg every other day, or 150 mg three times per week). An increased methadone dose may be required.

Efavirenz seems to lower plasma levels significantly (probably clinically relevant). However, this is not the case if fosamprenavir is boosted with ritonavir. If fosamprenavir + ritonavir are administered once daily, then the ritonavir dose should be increased to 300 mg. Caution in combination with lopinavir – plasma levels of both drugs are reduced. If dosed >400 mg daily, possibly dose reduction of ketoconazole/itraconazole. If fosamprenavir is boosted with ritonavir, ketoconazole and itraconazole maximum dose 200 mg daily. Caution in patients with sulfonamide allergy or with reduced liver function.

Comments: Except for diarrhea, this PI is well-tolerated. However, fosamprenavir currently does not play an important role in HIV medicine. One advantage of the drug is that there are no restrictions with respect to food intake.

Fortovase ®, see Saquinavir.

Foscarnet

Manufacturer: AstraZeneca.

Indications and trade name: reserve drug for induction and maintenance therapy of CMV retinitis. Severe acyclovir-resistant herpes or varicella zoster infections.

  • Foscavir® IV, 250 ml with 24 mg/ml.

Dose: 90 mg/kg IV over at least 2 hours BID for induction therapy (2-3 weeks) of CMV retinitis. 90-120 mg/kg over 2 hours QD for maintenance therapy.

HSV and HZV infections: 60 mg/kg IV BID for 2 weeks.

Side effects: nephrotoxicity, usually reversible after discontinuation. Electrolyte changes (hypocalcemia, hypokalemia) are also common. More rarely, anemia, neutropenia, fever, rash, headache, nausea, vomiting, diarrhea. Often painful penile ulcerations (washing recommended after every urination).

Interactions, warnings: good hydration. At least 2.5 l fluids daily. To prevent hypocalcemia give one ampule of 10% calcium solution in 100 ml 5% glucose immediately prior to infusion of foscarnet. Give 500-1000 ml 5% glucose before or after foscarnet dose. Do not mix infusions.

Initial monitoring of Na, K, Ca, creatinine, blood count at least 3 x week.

No concurrent treatment with other nephrotoxic drugs.

Adjust dose in renal insufficiency. See prescribing information.

Comment: Since the approval of valgancyclovir, foscarnet is only used rarely. However, it can be useful in some resistance situations (herpes viruses).

Foscavir®, see Foscarnet.

Fuzeon®, see T-20.

Gancyclovir

Manufacturer: Hoffmann-La Roche.

Indications and trade name: CMV retinitis.

  • Cymeven® IV, 500 mg

Dose: initial treatment with normal renal function: 5 mg/kg BID as an IV infusion for one hour. Treatment duration, 14 to 21 days.

Maintenance therapy: 6 mg/kg IV QD, 5 x week.

Side effects: leukopenia, anemia and thrombocytopenia are dose limiting. Nausea, vomiting or CNS symptoms such as confusion or headache are rare.

Interactions, warnings: monitor blood count every other day. Discontinue drug when below 500/µl (G-CSF if necessary). Contraindicated in neutropenia <500/µl, thrombocytopenia <25,000/μl and concurrent chemotherapy (KS, NHL). Do not combine with AZT and ddI (increased toxicity). Gancyclovir is a potential teratogen. Dose adjustment is necessary in renal insufficiency.

Comment: Since the approval of valgancyclovir, gancyclovir is only used rarely.

G-CSF

Manufacturer: Amgen, Chugai Pharma. Recently other companies (generics, biosimilars).

Indications and trade name: neutropenia, especially drug-induced (AZT, gancyclovir, interferon, myelosuppressive chemotherapy), rarely HIV-related.

  • Neupogen® prefilled syringe, 300 µg filgrastim (30 Mio I.U.) in 0.5 ml.
  • Neupogen® prefilled syringe, 480 µg filgrastim (48 Mio I.U.) in 0.5 ml.
  • Neulasta® prefilled syringe, 6 mg pegfilgrastim in 0.6 ml.
  • Granocyte® injection vial, 13.4 and 33.6 Mio I.U. lenograstim.

Dose: according to protocol for chemotherapy, usually approximately 5 µg/kg Neupogen®daily on fixed days. Outside of chemotherapy protocols, 1-5 µg/kg Neupogen®1-3 x week. The goal is usually at least 1000 neutrophil granulocytes/µl. For Granocyte® doses see product information.

Side effects: bone, back or muscle pain in 10 to 20% of patients, sometimes severe (requiring generous analgesia). Irritation at the injection site.

Comments: G-CSF is expensive. Long-term treatment should be avoided (change the drug causing neutropenia if possible). Remainders of individual ampules should be kept refrigerated in a syringe. Monitor blood count twice weekly. The recently approved biosimilars are less expensive!

Hivid®, see ddC.

Incivek®, see telaprevir.

Indinavir

Manufacturer: Merck.

Indications and trade name: HIV infection.

  • Crixivan® hard capsules, 200 mg and 400 mg

Dose: Two established dosages in combination with ritonavir:

800 mg BID plus 100 mg ritonavir BID.

400 mg BID plus 400 mg ritonavir BID.

Dose reduction is often possible with TDM. Dose without ritonavir (uncommon):

800 mg TID (two 400 mg capsules TID) one hour before or two hours after meals.

Side effects: nephrolithiasis (in up to 25%). Less frequently, nephrotoxicity with elevated serum creatinine. Diarrhea, nausea, vomiting. Hyperbilirubinemia. A sicca syndrome occurs relatively frequently (dry skin, mouth, eyes); ingrown toenails and paronychia; rarely alopecia. Lipodystrophy (originally called Crixbelly), dyslipidemia, disorders of glucose metabolism.

Interactions, warnings: At least 2 l of fluid should be consumed daily to prevent nephrolithiasis. The occurrence of nephrolithiasis and probably skin problems too, correlates with plasma levels. No concurrent administration with ddI.

In combination with ritonavir, indinavir can be taken twice daily with meals.

The concurrent use of rifampin, astemizole, terfenadine, cisapride, triazolam, ergotamines, simvastatin, lovastatin, or St. John’s wort is contraindicated.

The following dose adjustments are necessary: When using IDV/r, 150 mg rifabutin every 2 days or three times a week. Ketoconazole and itraconazole: 600 mg indinavir TID. Sildenafil: maximum 25 mg sildenafil/48h.

Comments: Was one of the first PIs on the market in 1996. Due to toxicity and ease of use, indinavir does not play a role any longer in HIV medicine.

Interferon alfa-2a/2b

Manufacturer: Essex (interferon a2b as Intron A®, pegylated as PegIntron®) and Roche (interferon a2a as Roferon®, pegylated as Pegasys®).

Indications and trade name: chronic hepatitis C (IFN a-2b and IFN a-2a), possibly also for chronic hepatitis B (α-2a). Kaposi’s sarcoma with good immune status (>250 CD4 cells/µl); pegylated interferons are not licensed for KS in Europe.

  • PegIntron® injector, 50, 80, 100, 120, 150 µg in 0.5 ml.
  • Pegasys® prefilled syringe, 135, 180 µg.
  • Roferon-A® prefilled syringe, 3, 4.5, 9, 18 Mio IU.
  • Intron A® pens, 18, 30, 60 Mio IU.

Dose: PEG-Intron®, 1.5 µg/kg body weight 1 x/week. Pegasys®, 180 µg 1 x/week

Standard interferons: 6 Mio IU 3 x/week.

Duration is dependent on success of treatment of KS, on HCV genotype and success of treatment. Interferon is injected subcutaneously.

Side effects: frequent side effects. Influenza-like symptoms such as fever and myalgia. Depression, even suicidal tendencies, fatigue, sleeping disorders, personality changes. Anemia, thrombocytopenia and leukopenia. Autoimmune thyroiditis. Reversible hair loss. Possibly impaired vision.

Interactions, warnings: influenza-like symptoms usually occur a few hours after dosing and can be reduced with paracetamol (take 1000 mg in advance). All side effects are usually reversible.

Contraindications are severe liver or renal dysfunction, severe heart disease, bone marrow disorders, CNS disorders (e.g., epilepsy, severe depression), uncompensated thyroid disorders.

Monitor blood count every two weeks initially, and then later, monthly with standard laboratory tests. TSH every three months. Interferons must be kept refrigerated.

Intelence®, see Etravirine.

Intron A®, see Interferon.

Invirase®, see Saquinavir.

Isentress®, see Raltegravir.

Isoniazid (INH)

Manufacturer and trade name: isoniazid is made by various manufacturers and has many trade names.

Indications: part of combination therapy for tuberculosis. Prophylactic treatment after tuberculin conversion.

  • Isozid comp® film-coated tablets, 200, 300, 400 mg INH and 40, 60, 80 mg vitamin B6 (pyridoxin-HCl)
  • Also in various combination preparations (see rifampicin)

Dose: 200 to 300 mg QD (4 to 5 mg/kg, maximum 300 mg) orally, IV only in severe cases during the first two weeks of therapy. For prophylaxis of neuropathy 100 mg pyridoxine orally QD. Pyridoxine is contained in the dosage of 20 mg per 100 mg of isoniazid in Isozid comp®.

Pediatric dose: 6 (to 10) mg/kg QD, maximum 300 mg.

Side effects: toxic hepatitis, more frequent in older patients, and patients with chronic liver disease and alcohol abuse. Peripheral neuropathy. Discontinue isoniazid in severe cases and treat for several weeks with pyridoxine and vitamin B-12. Psychosis, CNS symptoms. Fever, rash, nausea, vomiting, anemia, leukopenia, thrombocytopenia.

Interactions, warnings: INH should not be used in acute hepatitis and patients with a history of INH-associated hepatopathy or severe febrile reactions, peripheral neuropathy, macrohematuria. Always combine with vitamin B6.

Diverse interactions with barbiturates, cycloserine, theophylline, phenytoin and rifampin; doses of these drugs should be reduced due to CNS disorders.

Reduced absorption if taken concurrently with aluminum-based antacids.

Do not combine with ddI or d4T due to risk of peripheral neuropathy. Caution with alcohol during treatment.

Initially, biweekly monitoring of blood count, transaminases, bilirubin, and renal function. Discontinue isoniazid with elevation of transaminases to more than 3-fold initial levels and symptoms; or with a 5-fold elevation in the absence of symptoms.

Itraconazole

Manufacturer and trade name: diverse, with several trade names.

Indications: histoplasmosis, aspergillosis, treatment-resistant Candida infections (second choice). Also at derma/onychomycoses.

  • Sempera® capsules, 100 mg.
  • Sempera 7® capsules, 100 mg.
  • Sempera Liquid® juice, 10 mg/ml (150 ml).

Dose: Fluconazole-resistant Candida infections: 100 mg QD to 100 mg BID (up to 200 mg BID) ideally as itraconazole oral solution. Histoplasmosis, aspergillosis 200 mg BID.

Side effects: nausea, vomiting, rash, dizziness. Toxic hepatitis.

Interactions, warnings: To achieve maximum absorption, the capsules should be taken immediately after a full meal. Acidic drinks such as coke and orange juice may increase absorption.

No concurrent administration of itraconazole capsules with ddI, H2 blockers, omeprazole, antacids. No concurrent administration (of capsules or oral solution) with rifampin, rifabutin, carbamazepine, phenytoin, phenobarbital, simvastatin, lovastatin and isoniazid (these lower the bioavailability of itraconazole).

Itraconazole increases serum levels of cyclosporine, calcium antagonists, digoxin, lovastatin, simvastatin and indinavir. Itraconazole has a negative inotropic effect and should not be given to patients with heart failure.

Comments: Due to numerous interactions and unreliable plasma levels, administration of itraconazole is problematic. However, in contrast to fluconazole, it is effective for many non-albicans strains, aspergillosis, and histoplasmosis.

Kaletra®, see Lopinavir/r.

Kivexa® (US: Epzicom)

Manufacturer: ViiV Healthcare

Indications and trade name: HIV infection.

  • Kivexa® film-coated tablets, 600 mg abacavir and 300 mg 3TC.

Dose: 1 tablet QD. Replace Kivexa® with the individual drugs if kidney function is impaired (creatinine clearance below 50 ml/min), in order to adjust the 3TC dose.

Side effects: hypersensitivity reaction due to abacavir (see abacavir). Controversial data on a potentially enhanced risk of myocardial infarction in patients with an elevated risk of cardiovascular events. Otherwise well tolerated.

Comments: frequently-used fixed dose combination. The abacavir HSR has to be taken into account. However, HSR can be prevented by prior HLA-testing.

Klacid®, see Clarithromycin.

Lamivudine, see 3TC.

Lexiva®, see Fosamprenavir.

Lopinavir/r

Manufacturer: Abbott.

Indications and trade name: HIV infection.

  • Kaletra® film-coated capsules, 200 mg lopinavir + 50 mg ritonavir.
  • Kaletra® film-coated capsules, 100 mg lopinavir + 25 mg ritonavir.
  • Kaletra® solution, 80 mg lopinavir + 20 mg ritonavir per ml.

Dose: 2 capsules BID (400 mg lopinavir/100 mg ritonavir) or 5 ml solution BID. In the US, 4 capsules QD is approved. Tablets with a lower dose were developed for children (also known as Aluvia®).

Side effects: mainly diarrhea, nausea, dyslipidemia. More rare: headaches, and elevated transaminases.

Interactions, warnings: The solution should be kept in the refrigerator; this is not required for the tablets. No special food requirements.

Drug interactions are numerous. All drugs metabolized by the CYP3A or CYP2D6 enzyme systems are contraindicated: flecainide, propafenone, terfenadine, ergotamines, cisapride, midazolam, triazolam.

In combination with efavirenz (perhaps also nevirapine) the dose should be increased to 3 capsules BID or 6.5 ml solution BID. Measure plasma levels.

Rifampin and St. John’s wort reduce the blood levels of lopinavir.

Caution with: lovastatin, simvastatin (myopathy, rhabdomyolysis), carbamazepine, phenobarbital, phenytoin or sildenafil (hypotension), amiodarone, warfarin, lidocaine, tricyclic antidepressants, quinidine, cyclosporine, tacrolimus. Measure plasma levels in patients with reduced liver function tests or significantly elevated transaminases.

If lopinavir is combined with ddI, then the latter must be taken one hour before or two hours after lopinavir. Lopinavir solution contains alcohol, therefore no comedication with disulfiram or metronidazole. Caution with contraception – not safe. Increasing the methadone dose may be necessary.

When used with rifabutin, the rifabutin dose should be reduced by 75% (i.e., to 1 x 150 mg every two days).

Comments: Effective PI for both ART-naïve and pretreated patients and the only PI with a fixed dose of a ritonavir booster. Still one of the most prescribed drugs in HIV medicine. Disadvantages include gastrointestinal side effects (diarrhea) and the often significant dyslipidemia. As with all PIs, various drug interactions should be considered.

Maraviroc

Manufacturer: ViiV Healthcare.

Indications and trade name: In Europe, maraviroc is approved only for pretreated adult HIV-infected patients with CCR5-tropic HIV strains (R5). In November 2009, FDA has expanded use of maraviroc to include treatment-naïve patients with R5 viruses.

  • Celsentri® or Selzentry® tablets, 150 mg and 300 mg.

Dose: 300 mg BID with or without food. Depending on the co-medication, multiple dosage adjustments of maraviroc are recommended.

Combined Drugs Maraviroc dose adjustment
Nevirapine, tenofovir, other NRTIs none
Efavirenz + no protease inhibitors or other strong CYP3A4 inhibitors 600 mg BID
Rifampicin + no concurrent CYP3A4 inhibitor 600 mg BID
Boosted PIs (exception: tipranavir/r and fosamprenavir/r standard dosage) 150 mg BID
Efavirenz + simultaneous PI therapy (exception: fosamprenavir/r) 150 mg BID
Rifabutin + concurrent administration of PIs (exception: with tipranavir/r or fosamprenavir/r use standard dosage) 150 mg BID
Itraconazole, ketoconazole, clarithromycin, telithromycin 150 mg BID

In combination, the dosage varies according to the PI; when both an inhibitor and an inducer are given, the inhibitor dominates.

The following adjustments are recommended to reduced creatinine clearance:

Cr  Cl
(ml/min)

Without co-medication of a strong CYP3A4 inhibitor or together with tipranavir/r

Concurrent treatment with a strong CYP3A4 inhibitor, e.g.,
lopinavir/r, darunavir/r,
atazanavir/r, ketoconazole

Concurrent treatment with

saquinavir/r

50-80

no adjustment of

dosage interval

every 24 hours

every 24 hours

30-49

every 48 hours

<30

every 72 hours

Side effects: well tolerated, rare headaches, dizziness, fatigue, nausea. In high doses orthostatic hypotension. Occasional reports of CK increases, mycositis. Long-term data beyond 2-3 years is not yet available.

Interactions, warnings: the concurrent administration of maraviroc and rifampicin is not recommended. INH should be avoided (hepatotoxicity). St. John’s wort can lower maraviroc levels. The combination should be avoided.

It is required to have a valid tropism test indicating the presence of R5 viruses (genotyping generally suffices).

Comments: The first CCR5 antagonist and the first oral entry inhibitor that was licensed for HIV therapy. Since maraviroc inhibits only CCR5-tropic viruses, the co-receptor tropism has to be determined prior to treatment. Very well tolerated but complex dosage regulations.

Mavid®, see Clarithromycin.

Mycobutin®, see Rifabutin.

Nelfinavir

Manufacturer: Hoffmann-La Roche (Europe), Pfizer (US).

Indications and trade name: HIV infection.

  • Viracept® film-coated tablets, 250 mg.
  • Viracept® film-coated tablets, 625 mg (not in Europe).
  • Viracept Powder®, 50 mg/g.

Dose: 1250 mg BID (5 tablets) or 750 mg TID (3 tablets) with meals. Boosting with ritonavir is not useful.

Side effects: frequently reported diarrhea (>20%). Meteorism, nausea may also occur. Lipodystrophy, dyslipidemia, reduced glucose tolerance.

Interactions, warnings: contraindicated for co-medication with rifampin, the contraceptive pill, astemizole, terfenadine, cisapride, triazolam, ergotamines, simvastatin, lovastatin, and St. John’s wort. With rifabutin, 150 mg rifabutin QD and increase nelfinavir to 1250 mg BID or 1000 mg TID.

If withdrawal symptoms occur while on methadone dose may be increased.

Sildenafil maximum dose 25 mg in 48 h.

Diarrhea can often be controlled with loperamide (maximum 16 mg/day).

Comments: Nelfinavir is less potent than boosted PIs or NNRTIs. The main problems include frequent diarrhea and the high pill burden. May be useful in some pediatric patients (powder preparation) and during pregnancy. In 2007, nelfinavir was taken temporarily off the European market because of production problems. It is available again.

Neupogen®, see G-CSF.

Nevirapine

Manufacturer: Boehringer Ingelheim.

Indications and trade name: HIV infection. ART-naïve patients with a good immune status (women >250, men >400 CD4 T cells/µl) should avoid nevirapine because of an elevated risk of hepatotoxicity (see below).

  • Viramune® tablets, 200 mg.
  • Viramune Suspension®, 10 mg/ml.
  • Viramune® XR™ extended-release tablets, 400 mg.

Dose: 400 mg per day (1 tablet BID, 1 XR tablet OD). Always start with lead-in dosing (1 tablet 200 mg OD for 2 weeks) to reduce the frequency of rash. May be taken on an empty stomach or with meals.

Side effects: hepatotoxicity (elevation of transaminases 10-15%), rash. Caution is needed when both appear simultaneously (see below). Less frequently, fever, nausea, drowsiness, headache, myalgia. These side effects may occur with or without hepatotoxicity and/or rash. GGT elevation on nevirapine is almost always the rule.

To detect hepatotoxicity (an increase in transaminases to at least three times the upper limit of normal), liver function tests should be monitored biweekly for the first two months. Thereafter, monthly tests are necessary, as more than half of the hepatotoxic episodes occur after the first three months of treatment. If hepatotoxicity does occur, treatment must be interrupted until liver function tests have returned to initial levels. Treatment is restarted with 200 mg QD. The dose may be increased to 200 mg BID only after a prolonged period of observation. If liver enzymes increase again, nevirapine should be permanently discontinued. The risk is greater with good immune status (women >250 CD4 T cells/µl, 12-fold; men >400 CD4 T cells/µl, 5-fold). This elevated risk applies probably only to ART-naïve patients.

A mild rash, usually occurring within the first weeks of treatment, can be treated with antihistamines (e.g., Fenistil retard® 1 x 1 tablet) if mucous membranes are not involved and if transaminases are normal. Nevirapine must be discontinued if a severe rash occurs; in these cases, steroids are recommended (e.g., prednisolone 1 mg/kg for 3-5 days). Nevirapine should also be discontinued if other systemic symptoms occur (fever, conjunctivitis, myalgia, arthralgia, malaise). If the rash occurs during the first two weeks of treatment, then the dose should not be increased until the rash has resolved completely. Prophylactic treatment (steroids, antihistamines) is not advised.

Nevirapine has a favorable long-term profile. In particular, lipid levels are usually positively influenced. GGT is almost always increased during long-term treatment. Values of up to 150 U/l can be tolerated.

Interactions, warnings: cautious use in hepatic dysfunction (TDM can be used if available). No concurrent treatment with rifampin, ketoconazole, and St. John’s wort. Dose adjustment in combination with methadone (methadone dose increase may be required) and lopinavir/r (increase Kaletra® to 3 capsules BID). Nevirapine should not be given for post-exposure prophylaxis if there are other options.

Comments: Nevirapine is a frequently prescribed NNRTI, which is also used for the prevention of mother-to-child transmission. As with all NNRTIs, a single point mutation is sufficient for high-level resistance. During the first weeks of treatment, nevirapine is saddled with allergies and hepatotoxicity (start with lead-in dosing). However, the long-term tolerance is excellent (favorable lipid profile). In March 2011, the FDA approved extended-release tablets for OD use (in Europe, approval is still pending).

Norvir®, see Ritonavir.

Pegasys®, see Interferon.

PegIntron®, see Interferon.

Pentacarinat®, see Pentamidine.

Pentamidine

Manufacturer: Sanofi-aventis/GlaxoSmithKline.

Indications and trade name: treatment and secondary prophylaxis of Pneumocystis pneumonia if cotrimoxazole is contraindicated (hypersensitivity, resistance to treatment). Also for visceral leishmaniasis.

  • Pentacarinat® injection vials, 300 mg.

Dose: for treatment, 200-300 mg Pentacarinat® QD IV for five days (4 mg/kg), then halve the dose. In very mild cases, daily inhalations with 300 mg. In renal failure and creatinine clearance of 10 to 50 ml/min: 4 mg/kg q 24-36 h; below 10 ml/min: 4 mg/kg q 48 h. Prophylaxis: inhalation of 300 mg 1-2 x month.

Side effects: frequent with intravenous dosing. Nausea, vomiting, metallic taste; nephrotoxicity (increased creatinine in the second week of treatment) up to renal failure. Hypo- or hyperglycemia (possible even months after end of treatment), hypotension, arrhythmia, pancreatitis. Leukopenia and thrombocytopenia. Inhalation may induce cough, rarely asthma attacks.

Interactions, warnings: For inhalation, pentamidine as an aerosol is contraindicated in asthma. Inhalation is ineffective with several pulmonary diseases. Prior inhalation of a ß-mimetic (e.g., Berotec®) is desirable.

For infusions, caution with liver or renal failure, hyper- or hypotension, hyperglycemia, cytopenia. Always ensure sufficient intake of electrolytes and fluids. No concurrent administration of other nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, foscarnet). Patient should remain in supine position before, during and after infusions of pentamidine (caution: hypotension). Pentamidine should be infused slowly over at least 2 hours. Daily monitoring of BUN, serum creatinine, blood count, fasting blood glucose, urinalysis and serum electrolytes, weekly monitoring of bilirubin, alkaline phosphatase, transaminases.

Pyrimethamine

Manufacturer: GlaxoSmithKline.

Indications and trade name: prophylaxis and treatment of cerebral toxoplasmosis. Prophylaxis of Pneumocystis pneumonia.

  • Daraprim® tablets, 25 mg.

Dose: treatment of toxoplasmosis, Daraprim®2 tablets (50 mg) BID (for 3 days, then 1 tablet BID) + Leucovorin® 3 x 1 tablets/week each 15 mg + either sulfadiazine, clindamycin or atovaquone (second choice).

For PCP prophylaxis in combination with dapsone, Daraprim®2 tablets (50 mg) per week + Dapsone®1 tablet (50 mg) QD + Leucovorin® 2 tablets (30 mg) per week.

Side effects: nausea, colic, vomiting, diarrhea, leukopenia, anemia or thrombocytopenia. Rarely seizures, tremor or ataxia.

Interactions, warnings: pyrimethamine is contraindicated in megaloblastic anemia resulting from folic acid deficiency. Caution in patients with seizures, renal failure, asthma or G6PD deficiency. All patients taking pyrimethamine should receive folinic acid to decrease risk of myelosuppression. Folic acid is pointless, since it cannot be metabolized with pyrimethamine present.

Initial monitoring of blood count at weekly intervals.

Raltegravir

Manufacturer: Merck.

Indications and trade name: pretreated HIV patients. Since September 2009, raltegravir is approved also for treatment-naïve patients.

  • Isentress® film-coated tablets, 400 mg.

Dose: 1 tablet of 400 mg BID with or without food. In patients with renal or moderate hepatic impairment, no dose adjustment is required.

Side effects: Raltegravir is very well tolerated – in studies, there have generally been no more adverse events than seen with placebo. At a frequency of 1% to 10%, dizziness, stomach ache, flatulence, obstipation, hyperhidrosis, arthralgia, tiredness, weakness. Because of the dizziness, driving fitness may be (rarely) impaired. Rash (mild, very rarely requiring discontinuation). Recent FDA warning on suicidal thoughts. Case reports on rhabdomyolysis, hepatitis, insomnia.

Interactions, warnings: Raltegravir is eliminated for the most part via UGT1A1-mediated glucuronidation, so that relevant interactions with other antiretroviral agents are not expected. Strong inducers of UGT1A1 like rifampicin reduce plasma levels of raltegravir. If a combination is unavoidable, raltegravir dose should be doubled. Omeprazole or other gastric acid inhibitors may increase the plasma levels of raltegravir.

Comments: First-in-class integrase inhibitor. Well-tolerated and already an essential salvage agent, with impressive effectiveness in the setting of multiple resistance as well as in ART-naïve patients. Disadvantages: relatively low resistance barrier, no long-term data yet.

Rebetol®, see Ribavirin.

Ribavirin

Manufacturer: Roche and Essex.

Indications and trade name: chronic hepatitis C, only in combination with interferon. In Europe, the license for HIV/HCV-coinfected patients only applies to Copegus®.

  • Copegus® film-coated tablets, 200 mg, 400 mg.
  • Rebetol® hard capsules, 200 mg.
  • Rebetol® solution, 40 mg/ml.

Dose: daily dose 800 mg for body weight <65 kg, 1000 mg for 65-85 kg, 1200 mg for > 85 kg. Capsules are divided into two daily doses and taken with meals. Treatment duration depends on the genotype and success of treatment.

Side effects: the most frequent side effect is hemolytic anemia (Hb decrease by at least 2 g/dl obligatory), gastrointestinal complaints, headache and fatigue may also occur. Rarely lactic acidosis, pancreatitis in combination with NRTIs.

Interactions, warnings: ribavirin is contraindicated in severe coronary disease, renal failure, decompensated liver cirrhosis, and hemoglobinopathy. It is also contraindicated in pregnancy (teratogenicity).

Dose reduction for hemoglobin <10 g/dl. Reduce dose to 600-800 mg/day. Discontinue ribavirin at hemoglobin values <8.5 g/dl. Before reducing or discontinuing ribavirin, however, consider erythropoietin and transfusions. Avoid concurrent treatment with other myelosuppressive drugs (AZT).

Ribavirin can lead to lactic acidosis in combination with other NRTIs. Most importantly, ddI should be avoided while care should be taken with all other NRTIs like d4T. Possible antagonism with abacavir (mechanism unclear). Efavirenz-induced depression may worsen on ribavirin.

Monitoring of lab values (blood count, ALT, amylase, lipase) initially at biweekly intervals and then monthly. Measure lactate if unspecific symptoms occur.

Rescriptor®, see Delavirdine.

Retrovir®, see AZT.

Reyataz®, see Atazanavir.

Rifabutin

Manufacturer: Pfizer.

Indications and trade name: infections with Mycobacterium avium complex (MAC) in combination with other drugs (usually ethambutol and azithromycin). Also for patients with tuberculosis, when rifampicin is contraindicated.

  • Mycobutin® (previously, Alfacid®) capsules, 150 mg.

Dose: 300 mg rifabutin daily (+ azithromycin + ethambutol).

Renal failure, dose reduction by 50% for creatinine clearance <30 ml/min.

Dose adjustments for concurrent dosing with antiretroviral drugs:

Drug Recommendation
Atazanavir/r*, darunavir/r, fosampre-navir/r, indinavir/r, lopinavir/r, saqui-navir/r, tipranavir/r Rifabutin: 150 mg every other day or three times per week (see product information)
Nelfinavir Nelfinavir 1250 mg BID + rifabutin 150 mg/day
Delavirdine Rifabutin contraindicated
Efavirenz Increase rifabutin to 450 mg/day or 600 mg twice or three times weekly
Nevirapine Standard dose
* /r = boosted with ritonavir

Side effects: Nausea, vomiting, elevation of liver enzymes, jaundice. Uveitis usually only with a daily dose >300 mg and concurrent treatment with clarithromycin or fluconazole. Red discoloration of urine, skin and body secretions (inform patients about this).

Interactions, warnings: Rifabutin should not be used in thrombocytopenia and severe hepatic dysfunction. Monitor blood count and liver enzymes initially biweekly and then monthly.

Rifabutin can decrease the efficacy of the following drugs: analgesics, anticoagulants, corticosteroids, cyclosporine, digitalis (except digoxin), dapsone, oral antidiabetics, oral contraceptives, narcotic analgesics, phenytoin and quinidine. Erythromycin, ketoconazole, itraconazole, fluconazole and clarithromycin can increase plasma levels of rifabutin. Antacids should be taken at least three hours after rifabutin.

Rifampin

Manufacturer and trade name: manufactured by several companies, therefore many trade names, also part of several fixed dose combinations (see below).

Indications: tuberculosis. Use only in combination.

  • Rifa® tablets, 150, 300, 450, 600 mg Rifampicin.
  • Eremfat® syrup, 20 mg rifampicin per ml.
  • Eremfat® IV, 300 mg and 600 mg.
  • Rifinah® or Tebesium duo® film-coated tablets, 300 mg rifampicin +150 mg INH.
  • Rifater® or Tebesium trio® sugar-coated film-coated tablets, 120 mg rifampicin + 50 mg isoniazid + 300 mg pyrazinamide.

Dose: 600 mg daily (body weight >50 kg) or 450 mg (body weight <50 kg). Ideally taken in the morning on an empty stomach.

Side effects: toxic hepatitis (up to 20%), cholestatic changes. Red discoloration of urine and other body fluids (inform patients of this). Soft contact lenses may permanently stain red. Allergies are frequent. Gastrointestinal complaints such as nausea, vomiting, diarrhea.

Interactions, warnings: caution in patients with chronic liver disease. Discontinue rifampin if ALT >100 U/l or with elevated bilirubin (careful on re-exposure, gradually increasing doses is possible after normalization of values), and with patients who experience severe and persistent diarrhea (pseudomembranous colitis).

Rifampin should be avoided if concurrent NNRTIs or PIs are necessary.

Rifampin increases metabolism of numerous drugs, reducing their efficacy if administered concurrently. These drugs include atovaquone, warfarin, barbiturates, benzodiazepines, beta-blockers, clarithromycin, contraceptives, steroids, oral antidiabetics, cyclosporine, dapsone, digitalis, doxycycline, erythromycin, haloperidol, ketoconazole, methadone, phenytoin, theophylline, trimethoprim, verapamil.

Combination with ketoconazole or voriconazole is contraindicated.

Antacids, opiates and anticholinergics reduce the bioavailability of orally administered rifampin, if given simultaneously. To avoid this interaction, rifampin should be given several hours before these drugs.

Not for use in pregnancy.

Blood count and liver values should be monitored every two weeks.

Rilpivirine

Manufacturer: Janssen-Cilag

Indications and trade name: HIV infection.

  • Edurant® film-coated tablets, 25 mg rilpivirine (RPV).
  • Complera® film-coated tablets, 25 mg RPV + 200 mg FTC + 300 mg tenofovir.

Dose: 25 mg OD. Should be taken with a meal.

Side effects: Headache, insomnia. CNS symptoms occur less frequently than with efavirenz. A generally mild rash may occur in the first weeks (continued treatment is usually possible). Prolongation of the cardiac QTc interval was observed in studies of HIV-uninfected subjects given supratherapeutic doses of rilpivirine.

Interactions, warnings: An acidic gastric environment is necessary for absorption – PPIs should not be given to persons taking rilpivirine. Rilpivirine is a substrate of hepatic cytochrome P450 3A, so drugs that induce or inhibit the action of this isoenzyme may alter serum rilpivirine levels. Rifamycins (eg, rifampin and rifabutin), certain anticonvulsants (eg, carbamazepine and phenytoin), and St. John’s wort may substantially decrease rilpivirine concentrations and should be avoided. Macrolides, azole antifungals and PIs may increase rilpivirine levels.

Comments: Rilpivirine is a new NNRTI which was approved by the FDA in May 2011 (approval in Europe still pending). As with the other members of this drug class, drug interactions, a low resistance barrier and cross-resistance have to be considered. Will probably be used almost exclusively in FDCs (Complera®).

Ritonavir

Manufacturer: Abbott.

Indications and trade names: HIV infection. Also a component of Kaletra®.

  • Norvir® soft gel capsules, 100 mg.
  • Norvir® tablets, 100 mg.
  • Norvir® oral solution, 80 mg per ml (7.5 ml = 600 mg).

Dose: in rare cases, when ritonavir is used as a single PI, the dose is 600 mg BID (increase dose over two weeks: 300 mg BID on day 1-2, 400 mg BID on day 3-5, 500 mg BID on day 6-13). However, ritonavir should ideally be used only for boosting of other PIs. Daily doses in combination with:

  • Atazanavir (Reyataz®, 300 mg QD), 100 mg ritonavir QD
  • Darunavir (Prezista®, 600 mg BID), 100 mg ritonavir BID
  • Darunavir (Prezista®, 800 mg QD), 100 mg ritonavir QD
  • Fosamprenavir (Telzir®, 700 mg BID), 100 mg ritonavir BID, also 1400 mg fosamprenavir QD + 200 mg QD (US only, naive patients)
  • Indinavir (Crixivan®, 800 mg BID), 100 mg ritonavir BID, also 400 mg ritonavir BID + 400 mg indinavir BID
  • Lopinavir (Kaletra®) fixed combination, see Lopinavir/r.
  • Saquinavir (Invirase®, 1000 mg BID), 100 mg ritonavir BID
  • Tipranavir (Aptivus®), 200 mg ritonavir BID

Side effects: depending on dosage, frequent, nausea, vomiting, diarrhea, perioral paresthesia and electric sensations on arms and legs. Elevated transaminases and GGT, dyslipidemia, lipodystrophy and rarely diabetes mellitus.

Interactions: even the low boosting doses have multiple drug interactions. The following drugs are contraindicated: rifampin, amiodarone, astemizole, bepridil, terfenadine, encainide, flecainide, cisapride, triazolam, ergotamine, simvastatin, lovastatin, quinidine and St. John’s wort. Sildenafil should be avoided.

Caution should be taken and plasma levels measured for both ritonavir and (if possible) the following co-medications: methadone, immunosuppressants (cyclosporine, tacrolimus), macrolide antibiotics (erythromycin, clarithromycin), steroids, calcium antagonists, tricyclic antidepressants, other antidepressants,  neuroleptics (haloperidol, risperidone, thioridazine), antimycotic drugs (ketoconazole, itraconazole), carbamazepine, tolbutamide, rifabutin, theophylline, and warfarin.

Comments: One of the first PIs. The dosage required to inhibit HIV replication is too toxic. Today ritonavir should only be used as booster for other antiretroviral drugs (mainly PIs). Numerous interactions.

Saquinavir

Manufacturer: Hoffmann-La Roche.

Indications and trade name: HIV infection.

  • Invirase 500® film-coated tablets, 500 mg saquinavir.

Dose: 1,000 mg saquinavir BID + 100 mg ritonavir BID.

Side effects: mainly gastrointestinal, diarrhea, nausea, abdominal discomfort, meteorism. Otherwise well-tolerated. Rarely elevation of transaminases or gGT, headache. As with other PIs, lipodystrophy, dyslipidemia and reduced glucose tolerance may occur with long-term treatment.

Interactions, warnings: contraindicated with rifampin, astemizole, terfenadine, cisapride, triazolam, ergotamine, simvastatin, lovastatin, and St. John’s wort. If saquinavir is not combined with other PIs it should be taken with meals.

Comments: saquinavir was the first PI to be licensed for HIV therapy in 1995. It is well-tolerated, except for gastrointestinal problems, and typically not associated with any serious short-term problems. Still recommended in several guidelines. However, pill burden is high, compared to other PIs.

Sempera®, see Itraconazole.

Sobelin®, see Clindamycin.

Stavudine, see d4T.

Stocrin®, see Efavirenz.

Sulfadiazine

Manufacturer: Heyl.

Indications and trade name: treatment and prophylaxis of cerebral toxoplasmosis, only in combination with pyrimethamine.

  • Sulfadiazin-Heyl® tablets, 500 mg.

Dose: For treatment, 2-3 500 mg tablets QD (= daily dose 4-6 g). For prophylaxis, halve the dose (500 mg QD).

Renal insufficiency: creatinine clearance 10-50 ml/min: halve dose, <10 ml/min: one third of the dose.

Side effects: very frequently allergies with pruritus, fever and urticaria, often treatment-limiting. Rarely Stevens Johnson syndrome. Nausea, vomiting, diarrhea. Renal problems with renal failure, crystalluria, nephrolithiasis in up to 7%. Anemia, leukopenia, thrombocytopenia. Elevated liver enzymes.

Interactions, warnings: sulfadiazine is contraindicated in sulfonamide hypersensitivity in G6PD deficiency, renal failure, severe hepatic disease or dysfunction (e.g., acute hepatitis) and during pregnancy and breastfeeding.

Sulfadiazine can increase the effect of sulfonylurea urea (oral antidiabetics), anticoagulants, diphenylhydantoin. Concurrent use of antacids reduces absorption of sulfadiazine (separate administration by 1-2 hours). Ensure sufficient intake of fluids (at least 2 l daily).

Initially, monitor blood count, ALT, creatinine, and BUN at least weekly.

Monitor urine. In case of crystalluria, alkalize urine.

Sustiva®, see Efavirenz.

T-20 (enfuvirtide)

Manufacturer: Hoffmann-La Roche.

Indications and trade name: treatment of patients with evidence of HIV replication despite ongoing ART with at least one PI, any NRTI or NNRTI.

  • Fuzeon®  90 mg/ml powder and solvent.

Dose: 90 mg subcutaneously BID.

Side effects: generally well-tolerated. However, almost all patients have local injection site reactions: erythema, inflammation, induration, rash. In the licensing studies, approximately 10% of patients required intermittent use of analgesics or were temporarily affected in their daily activities.

Patients on T-20 may have an increased risk of bacterial pneumonia. It is important to be particularly vigilant in patients with risk factors for pneumonia (low baseline CD4 counts, high viral load, IV drug users, smokers, history of pulmonary disease).

Hypersensitivity reactions with rash, fever, nausea, chills, hypotension or elevated transaminases are rare (< 1%).

Interactions, warnings: interactions are not known. Injection sites – upper arm, ventral hip, and abdomen. Change injection sites often. On the back, possibly fewer irritations. Do not inject at sites with inflammatory signs from previous injections. Do not inject at sites with birth marks, scars or disrupted skin integrity.

Comments: T-20 is an entry inhibitor used for heavily treatment-experienced patients. T-20 must be injected subcutaneously BID. Use is limited primarily by its administration and by the local skin side effects. Very expensive, may double the price of ART.

Telaprevir

Manufacturer: Janssen-Cilag/Vertex.

Indications and trade name: as a component in a combination therapy with peginterferon alfa and ribavirin for patients with chronic hepatitis C, genotype 1. Incivek® must be administered with both peginterferon alfa and ribavirin for all patients for 12 weeks, followed by a response-guided regimen of either 12 or 36 additional weeks of peginterferon alfa and ribavirin depending on viral response and prior response status.

  • Incivek® film-coated tablets, 375 mg.

Dose: 750 mg taken 3 times a day (7-9 hours apart) with food (not low fat). To prevent treatment failure, the dose must not be reduced or interrupted. When combined with efavirenz, telaprevir dose should be increased to 1250 mg 3-times-daily.

Side effects: Nausea, vomiting, fatigue, diarrhea, pruritus, anemia. Mild skin rashes are common, leading to discontinuation of the drug in up to 7 %. However, serious skin reactions (DRESS, Stevens-Johnson Syndrome) were reported in less than 1%. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended.

Interactions, warnings: do not use in other HCV genotypes than genotype 1.

Telaprevir AUC decreased significantly when administered with lopinavir/r, darunavir/r or fosamprenavir/r but not with atazanavir. Darunavir and fosamprenavir levels fell by more than half when co-administered with telaprevir. When combined with efavirenz, telaprevir dose should be increased to 1250 mg 3-times-daily. Ritonavir alone did not significantly boost telaprevir levels. Incivek® is contraindicated when combined with drugs that are highly dependent on CYP3A for clearance, such as rifampicin, ergot derivates, atorvastatin, lovastatin, simvastatin, orally administered midazolam, or triazolam.

Comments: New HCV NS34A protease inhibitor which was approved by the FDA in May 2011. In Europe, approval is expected for October of 2011. When combined with peginterferon alfa and ribavirin, SVR rates increase by 20-40 % in treatment naïve and experienced patients. Due to numerous toxicities of the triple HCV therapy, the use of telaprevir is only recommended in experienced centers. Data on HIV-infected patients still limited.

Tenofovir

Manufacturer: Gilead Sciences.

Indications and trade name: HIV infection, chronic hepatitis B.

  • Viread® film-coated (fc) tablets, 300 mg tenofovir disoproxil fumarate.
  • Truvada® fc tablets, 300 mg tenofovir + 200 mg FTC.
  • Atripla® fc tablets, 300 mg tenofovir + 200 mg FTC + 600 mg efavirenz.
  • Complera® fc tablets, 300 mg tenofovir + 200 mg FTC + 25 mg rilpivirin.

Dose: 300 mg QD, to be taken with a meal. Dose adjustments in patients with renal impairment are required. Double dosage interval (every 48 hours) at moderate kidney dysfunction (creatinine clearance 30-49 ml/min, below 30 ml/min it should be avoided). In hemodialysis patients, every 7 days following completion of hemodialysis.

Side effects: generally well-tolerated. Rarely, renal side effects (renal failure, tubulopathies including Fanconi’s syndrome, nephrogenic diabetes insipidus). Bone loss, osteomalacia. Rarely, elevation of liver enzymes. CK rises observed in up to 48% (macro CK, relevance is unclear).

Interactions, warnings: Patients with existing renal disease should either not receive tenofovir or, with no alternatives, reduce the dose. Controls (creatinine clearance and serum phosphate) before starting therapy, during the first year of treatment every four weeks and thereafter every three months.

When serum phosphate is <1.5 mg/dl (0.48 mmol/l) or creatinine clearance <50 ml/min check renal function again within one week. Simultaneous determination of blood glucose and potassium, as well as glucose in the urine. Interruption of therapy may be necessary, if creatinine clearance is <50 ml/min or serum phosphate is <1.0 mg/dl (0.32 mmol/l).

Creatinine clearance in ml/min is calculated as follows:

Women: (1.04 x (140 – age) x kg) / creatinine (µmol/l)

Men: (1.23 x (140 – age) x kg) / creatinine (µmol/l)

Concurrent administration of tenofovir and drugs that are also eliminated via active tubular secretion can lead to increased serum concentrations of both drugs: cidofovir, acyclovir, valacyclovir, gancyclovir, valgancyclovir.

Do not combine with ddI, co-medication with tenofovir increases the AUC of ddI by 44%. Atazanavir and lopinavir increase tenofovir levels. Tenofovir lowers the plasma levels of atazanavir (always boost with 100 mg of ritonavir).

Comments: One of the most frequently used drugs in HIV medicine. Good tolerability profile and only low mitochondrial toxicity. However, potential nephrotoxicity has to be taken into account as well as some interactions (particularly with ddI and atazanavir). Tenofovir is also effective against hepatitis B virus; in April 2008, it was officially licensed for hepatitis B therapy.

Tipranavir

Manufacturer: Boehringer Ingelheim.

Indications and trade name: HIV-infected adults who are either highly treatment-experienced or who have multiple PI resistance.

  • Aptivus® capsules, 250 mg.

Dose: 500 mg BID + 200 mg BID ritonavir with meals.

Side effects: The most frequent side effects are gastrointestinal, diarrhea and nausea. Elevated transaminases have been observed in at least 6% of patients, with clinical hepatitis and liver failure in rare cases. More frequent than with other PIs dyslipidemia (20%). Rare rash (urticarial or maculopapular). Occasional reports (and FDA warning) of intracranial bleedings (causality unclear).

Interactions, warnings: Tipranavir is a substrate, activator and inhibitor of cytochrome CYP3A and both a substrate and inhibitor of the P-glycoprotein. Consequently, various interactions have to be taken into account (see table). Tipranavir reduces the serum level of other PIs, so a double PI regime is not applicable. Fluconazole and clarithromycin increase the serum level of tipranavir. Antacids reduce the tipranavir levels by 30% (administer separately).

Drugs contraindicated on tipranavir therapy:

Antiarrhythmics Amiodarone, bepridil, flecainide, propafenone, quinidine
Antihistamines Astemizole, terfenadine
Ergotamine derivatives (Dihydro)-ergotamine, (methyl)-ergonovine
Prokinetics Cisapride
Neuroleptics Pimozide
Sedatives/hypnotics Midazolam, triazolam

Rifampicin reduces tipranavir levels by 80% (avoid). Tipranavir/r increases the serum levels of atorvastatin by 8-10 fold (use another statin like pravastatin or fluvastatin). Dose reduction by at least 75% for rifabutin: 150 mg every other day or three times per week. Tipranavir reduces the plasma levels of abacavir and AZT by 35-40% (relevance unclear).

Tipranavir should not be used in patients with moderate to severe hepatic impairment (Child-Pugh B and C). Use cautiously in patients with HBV or HCV coinfection. Determine liver function parameters (monthly during the first 6 months), transaminases, cholesterol and triglycerides before and during treatment. Women who take an estrogen-based contraceptive appear to have a higher incidence of rash.

Comments: Tipranavir is the first non-peptidic PI. In two large studies on intensively PI-experienced patients, it was superior to optimized background regimen. Helpful salvage agent. Tipranavir has to be boosted with elevated ritonavir doses. Numerous interactions have to be taken into account.

Trizivir®

Manufacturer: ViiV Healthcare.

Indications and trade name: HIV infection.

  • Trizivir® film-coated tablets, 150 mg 3TC + 300 mg AZT + 300 mg ABC

Dose: 1 tablet BID. In cases of impaired renal function (creatinine clearance less than 50 ml/min), the individual drugs should be given separately to allow for dose adjustment of 3TC.

Side effects: mostly gastrointestinal, see individual drugs. Abacavir HSR (see abacavir). There are possibly additive effects with regard to mitochondrial toxicity. Possibly an increased risk for cardiovascular events (see abacavir).

Comments: Less effective than multi-class combinations. No longer recommended without a PI/r or NNRTI. Further disadvantages include mitochondrial toxicity, abacavir HSR, QD is not possible. Thus, Trizivir® is only indicated in patients with compliance problems or with interactive co-medication (for tuberculosis; coumarin derivatives, etc).

Truvada®

Manufacturer: Gilead (Truvada®)

Indications and trade name: HIV infection.

  • Truvada® film-coated tablets, 300 mg tenofovir + 200 mg FTC.

Dose: 1 tablet QD. Caution in patients with renal dysfunction. If there are no alternatives, with a reduced creatinine clearance of 30-49 ml/min, then it is recommended to reduce the dose to 1 tablet every two days (<30: avoid Truvada®). Absorption of Truvada® not affected by food intake.

Side effects: monitoring of renal parameters, see tenofovir.

Interactions, warnings: see tenofovir. In patients coinfected with chronic hepatitis B, Truvada® is preferred. Exacerbation of hepatitis may occur after discontinuing Truvada®.

Comments: Combination pill consisting of tenofovir and FTC. To date, one of the most frequently prescribed HIV drugs. Well-tolerated. However, renal dysfunction and bone loss may occur (see tenofovir).

Valcyte®, see Valgancyclovir.

Valgancyclovir

Manufacturer: Hoffmann-La Roche.

Indications and trade name: induction and maintenance therapy of CMV retinitis.

  • Valcyte® tablets, 450 mg.

Dose: for induction therapy 900 mg BID for 3 weeks (or until scar formation of CMV lesions), then suppressive therapy with 900 mg QD. Should be taken with a meal. The following doses should be used for renal failure:

Cr Cl (ml/min) Induction therapy Suppressive therapy
>60 900 mg BID 900 mg QD
40–59 450 mg BID 450 mg QD
25–39 450 mg QD 450 mg q 48 h
10–24 450 mg q 48 h 450 mg 2 x week

 

Side effects: frequent leukopenia, also thrombocytopenia, anemia. Gastrointestinal complaints such as nausea, vomiting and diarrhea are more frequent than with intravenously-administered gancyclovir.

Interactions, warnings: monitoring of blood count at least 2-3 x week during induction. Discontinuation if neutrophils below 500/µl (G-CSF if needed). Contraindicated in neutropenia <500/µl, thrombocytopenia <25,000/µl and concurrent chemotherapy.

Caution when concurrent dosing with ddI, as valgancyclovir can double levels of ddI (increased toxicity). Valgancyclovir is potentially teratogenic and carcinogenic; reliable contraception is required.

The drug is extremely expensive. It should be discontinued when sufficient immune reconstitution has been reached (see chapter on OIs).

Comment: Valgancyclovir was the first effective anti-CMV drug to be administered orally. Valgancyclovir is a prodrug of gancyclovir and therefore has a similar toxicity profile, neutropenia, anemia and thrombocytopenia.

Victrelis®, see Boceprevir.

Videx®, see ddI.

Viracept®, see Nelfinavir.

Viramune®, see Nevirapine.

Viread®, see Tenofovir.

Vistide®, see Cidofovir.

Zerit®, see d4T.

Ziagen®, see Abacavir.

Zidovudine, see AZT.

Zovirax®, see Acyclovir.

Leave a comment

Filed under 35. Drug Profiles, Part 6 - Drugs