30 September 2014
Prezcobix available in Canada—What you need to know
In September 2014, Janssen Inc. began marketing a new medicine called Prezcobix in Canada. This medicine contains the following two drugs:
- darunavir 800 mg (also called Prezista) – an HIV protease inhibitor
- cobicistat 150 mg – a boosting agent
Prezcobix is meant to be used as part of a regimen of anti-HIV drugs in adults. Prezcobix is taken once daily with food; the type or amount of food does not matter. For some people with HIV, combining darunavir and cobicistat can help simplify regimens by putting two drugs into one pill. The price of Prezcobix will be the same as the current combined price of darunavir and low-dose ritonavir. Darunavir without cobicistat will continue to be available.
Darunavir is the leading anti-HIV protease inhibitor in Canada and Western Europe. It has been used by thousands of people over the past eight years. In clinical trials, darunavir-based regimens have been shown to be powerful and generally safe when used as directed. Darunavir-based regimens have been tested in people new to HIV medicines as well as people who have used treatment in the past. Darunavir has been taken with a low dose of another drug called ritonavir (Norvir). The purpose of the low dose of ritonavir is to boost and maintain the levels of darunavir in the blood. In this way, darunavir need only be taken once daily. When drugs such as ritonavir are used in this way they are called boosters or boosting agents. Ritonavir has been commonly used for the past decade to boost other HIV protease inhibitors such as atazanavir (Reyataz) and lopinavir (Kaletra). Now, an alternative to boosting with ritonavir has become available—the drug cobicistat.
Cobicistat is a relatively new boosting agent. It is sufficiently powerful that only a once-daily dose is needed to boost and maintain the level of darunavir in the blood. Cobicistat is also used as a booster in another HIV medicine called Stribild, where it boosts the level of a drug called elvitegravir. To date cobicistat has only been available coformulated with another drug.
In studies that have occurred or are underway, cobicistat-boosted regimens have been found to be similarly effective as ritonavir-boosted regimens. In particular, regimens containing cobicistat-boosted darunavir have been found to be similar in effectiveness and safety to regimens containing ritonavir-boosted darunavir.
Clinical trials have found that the absorption of the ingredients in Prezcobix is similar to that seen when ritonavir-boosted darunavir is taken.
In one phase III clinical trial (called GS-US-216-0130) researchers evaluated the safety and effectiveness of Prezcobix together with two nucleoside analogues (nukes). In this study, all medicines were taken once daily with food. Researchers recruited 313 participants—295 who had never previously used treatment and 18 others who were treatment experienced. The majority of participants were men (89%) and 11% were women.
Researchers found that after 24 weeks of this therapy, 82% of participants had a viral load less than 50 copies/ml. This degree of overall response is similar to what has been seen in clinical trials of ritonavir-boosted darunavir or other modern anti-HIV drugs. About 12% of participants had virologic failure and the remaining participants left the study for different reasons.
In a phase III clinical trial when Prezcobix was used as part of combination therapy, it was well tolerated. Most side effects reported were mild in intensity. Here are some side effects that were at least of moderate intensity, occurring in the following proportions of patients:
- diarrhea – 5%
- rash – 5%
- headache – 3%
- nausea – 4%
- vomiting – 2%
Generally moderate increases of the following laboratory tests occurred in the following proportion of participants:
- amylase (an enzyme produced by the pancreas gland) – 7%
- total cholesterol – 11%
- LDL-cholesterol – 11%
- glucose (sugar) – 7%
- AST (aspartate aminotransferase, a liver enzyme) – 6%
Hepatitis B and C viruses
Co-infection with hepatitis B and/or C virus occurs among some HIV-positive people. The pharmaceutical company Janssen notes that generally “patients with pre-existing liver dysfunction including chronic hepatitis B or C have an increased frequency of [elevated levels of liver enzymes in their blood] during combination [anti-HIV therapy].”
Janssen recommends that doctors consider increased monitoring if Prezcobix is prescribed in patients with the following medical issues:
- elevated liver enzymes in the blood prior to starting Prezcobix
- active hepatitis B and/or C virus
- underlying liver disease
Janssen says that if cases of “new or worsening liver dysfunction, including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and [swollen liver and/or spleen]” occur in patients taking Prezcobix, doctors should be prompted to consider “interrupting or discontinuing treatment.”
Historically, about 10% of people who have used darunavir with ritonavir in clinical trials have developed rash. Janssen states that this rash “was mostly mild-to-moderate, often occurring within the first four weeks of [initiating] treatment and resolving with continued dosing.” Less than 1% of patients who developed this rash have had to stop taking darunavir.
In rare cases, severe rash may be accompanied by one or more of the following symptoms:
- lack of energy
- achy muscles or joints
- blisters on the skin
- peeling skin
- oral lesions
- eye inflammation
- belly pain
If you are taking Prezcobix and these symptoms occur, call your doctor right away. If your doctor is not available go immediately to the emergency room of the nearest hospital. If you are unable to do this, dial 911.
Focus on the kidneys
The kidneys filter the blood, putting waste materials into urine and reabsorbing nutrients and other useful material back into the blood.
Prezcobix contains cobicistat, which can interfere with the ability of the kidneys to release the waste product creatinine into urine. Therefore, a small but persistent increase of creatinine can be detected in the blood of Prezcobix users. This small increase is generally not considered harmful. Furthermore, the small increase in creatinine does not appear to affect the kidneys’ ability to filter other substances from the blood. A similar effect on the kidneys is seen with the anti-HIV medicines Stribild (which contains cobicistat) and dolutegravir (Tivicay and in Triumeq), as well as in the anti-ulcer medicine cimetidine (Tagamet).
For further information about kidney safety, see the “Monitoring the kidneys” section later in this bulletin.
Women and other groups
In clinical trials of Prezcobix, no side effects specific to women have been reported. In previous studies with darunavir-containing regimens, no side effects specific to gender or race were detected.
Prezcobix has not been studied in pregnant women. Therefore, its safety in this population is not known. The manufacturer recommends that Prezcobix should not be used during pregnancy “unless the potential benefit justifies the risk.”
Prezcobix is meant for use in adults. The manufacturer notes that in clinical trials only a relatively small number of participants over the age of 65 have used Prezcobix. In general, the major organ systems—heart and circulatory system, lungs, liver, kidneys—may not work as well in older people as they do in healthy younger people. Janssen provides the following advice:
“In general, caution should be exercised in the administration and monitoring of Prezcobix in elderly patients.”
Understanding drug interactions
Sometimes one drug can interfere with the body’s processing of another drug. Such an effect is called a drug–drug interaction or, more simply, a drug interaction. This can result in higher-than-normal levels of one or both drugs in the blood, resulting in side effects or worsening of pre-existing side effects. Alternatively, the interference of one drug on another can cause the levels of one or both drugs to fall below normal levels. This can result in the drug(s) losing effectiveness. In the case of HIV medicines, this fall in drug level(s) can cause HIV to develop the ability to resist one drug and, likely, other related drugs. This resistance limits future treatment options.
To minimize the development of resistance, all prescribed medicines should be taken every day, exactly as directed.
Always tell your doctor and nurse about all the drugs you are taking, both prescription and over the counter as well as any supplements or herbs. Pharmacists can be very helpful in checking for the possibility of drug interactions.
Prezcobix drug interactions
The medicines in Prezcobix interfere with a key enzyme (called CYP3A4) in the liver and intestines. Many drugs are broken down by this enzyme. As Prezcobix slows the activity of this enzyme, it causes levels of other drugs in the body to increase. This can result in what Janssen calls “serious and life-threatening reactions.” Janssen warns that the following drugs should not be used by people who are also taking Prezcobix because of the high risk for severe reactions:
Other HIV drugs
- atazanavir (Reyataz)
- indinavir (Crixivan)
- lopinavir (Kaletra)
- ritonavir (Norvir)
- saquinavir (Invirase)
Abnormal heart rhythm drugs
Drugs for asthma and bronchitis
- salmeterol (Advair, Serevent)
Drugs for enlarged prostate (benign prostatic hyperplasia, or BPH)
St. John’s wort or its extracts (hypericin and hyperforin) can greatly reduce the amount of darunavir in the blood. Assume that other herbs can interact with Prezcobix and other medicines until clinical trials are done to assess their potential for interactions.
Drugs for treating pulmonary hypertension
- sildenafil (Revatio)
Statins (cholesterol-reducing drugs)
There may be other potential drug interactions with Prezcobix and doses of other drugs may need to be adjusted. Speak to your pharmacist and doctor for more information.
A note on resistance testing
Janssen recommends that HIV resistance testing be done particularly before prescribing Prezcobix to treatment-experienced patients. If resistance testing is not available but Prezcobix must be prescribed, then Janssen recommends that Prezcobix only be prescribed to patients who have never been treated with HIV protease inhibitors.
Each tablet of Prezcobix contains 800 mg of darunavir and 150 mg of cobicistat. For adults prescribed Prezcobix the recommended dose is one tablet per day taken with food; the type and amount of food does not matter. To help integrate Prezcobix into your life, it may be simplest to take it with a meal. You can also take Prezcobix with a snack – a piece of fruit, a few crackers, a slice of bread with margarine, peanut butter or butter, vegetables, a chocolate bar, a granola bar, a sandwich, a bowl of soup and so on.
Prezcobix is meant to be used together with other anti-HIV drugs.
Janssen has stated that kidney injury can sometimes occur or grow worse when the anti-HIV drug tenofovir (in Viread and Truvada) is taken by people who are also taking Prezcobix. The pharmaceutical company makes the following recommendations for physicians concerning Prezcobix and monitoring the kidneys:
- “Do not initiate cobicistat as part of a regimen containing tenofovir in patients who have [an eGFR (estimated glomerular filtration rate)] below 70 mL/min.”
- Assess the amount of glucose and protein in the urine before starting therapy and then “perform routine monitoring [eGFR, glucose and protein in urine] during treatment when cobicistat is used with tenofovir.”
- Assess the amount of phosphorus in the blood of patients “at risk for renal impairment.”
- Avoid the use of cobicistat with tenofovir in (1) combination with drugs that have the potential to injure the kidney, or (2) in patients who have recently used drugs with the potential to injure the kidneys.
The long and winding road
Currently, although Prezcobix is licensed in Canada, physicians can prescribe it but patients must pay for it unless their private insurance plan provides coverage. If left untreated, HIV infection leads to catastrophic disease that can affect people’s ability to work and requires expensive care. In Canada, provincial and territorial ministries of health heavily subsidize the cost of anti-HIV medications. Each ministry has a listing of drugs for which it is prepared to pay. These listings are called formularies.
After Health Canada approves a drug it must then undergo additional reviews before it can be listed on provincial and territorial formularies. Prezcobix is currently in queue for these reviews.
It will therefore be several months before Prezcobix is listed on provincial and territorial formularies. Check with your pharmacist or physician to find out if Prezcobix is listed on the formulary in your region.
Prezcobix is currently available from pharmacies.
For the future
Prezcobix represents an advance for convenience and simplicity—two major medicines in one pill taken once a day. However, more companies are moving towards developing entire regimens in one pill taken once daily. Janssen is sponsoring clinical trials of Prezcobix as part of an entire regimen in a single pill taken once daily.
Janssen is also cooperating with another company, ViiV Healthcare, to develop a regimen that can be taken just once a month. Clinical trials are underway to explore this idea. However, it will likely be several years before such regimens become available.
—Sean R. Hosein
- Janssen. Prezcobix (darunavir/cobicistat). Product Monograph. 18 June 2014.
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- Spreen WR, Margolis DA, Pottage JC Jr. Long-acting injectable antiretrovirals for HIV treatment and prevention. Current Opinion in HIV/AIDS. 2013 Nov;8(6):565-71.
- Kakuda TN, Van De Casteele T, Petrovic R, et al. Bioequivalence of a darunavir/cobicistat fixed-dose combination tablet versus single agents and food effect in healthy volunteers. Antiviral Therapy. 2014; in press.
- Kakuda TN, Brochot A, Tomaka FL, et al. Pharmacokinetics and pharmacodynamics of boosted once-daily darunavir. Antimicrobial Agents and Chemotherapy. 2014 Oct;69(10):2591-2605.
- Pozniak A, Markowitz M, Mills A, et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial. Lancet Infectious Diseases. 2014 Jul;14(7):590-9.