Darunavir - Dosages, Indications, Contraindications, Pharmacology, and Side Effects

Overview

Darunavir is an antiretroviral drug that sorts with a class of protease inhibitors. It is generally used in conjugation with Ritonavir or other antiretroviral drugs for attaining full efficacy and enhancement. This drug therapy suppresses the amount and activity of human immunodeficiency virus (HIV) in the bloodstream. Darunavir does not indulge in curing HIV but reduces the risk of progressing acquired immunodeficiency syndrome (AIDS). In addition, the drug is known to decrease the probability of HIV-allied opportunistic infection and cancers.

So, it is used in the treatment and prevention aspects of HIV infection. The first protease inhibitor to be approved by FDA was the drug Saquinavir. Arun K. Gosh discovered the molecule Darunavir at the University of Illinois. Then, the drug received FDA approval in June 2006. So, it was approved for medical use in the United States in 2006 and in the European Union in 2007. Darunavir holds a position on the essential medicine list of the World Health Organization.

How Does Darunavir Work?

Darunavir is an antiretroviral agent that comes in a tablet and oral suspension with various dosages. The doctors prescribe Darunavir with Ritonavir and other antiretroviral agents to treat HIV infection. Generally, Darunavir is not used alone but with coadministration since Ritonavir increases the potency and efficacy of Darunavir. Also, this combination is chiefly introduced to an HIV treatment-experienced naive. Darunavir does not cure but reduces the risk of AIDS.

Darunavir belongs to a class of drugs called protease inhibitors. The protease inhibitors reduce the amount of HIV in the bloodstream and elevate the CD4 cell concentration by suppressing the growth of an HIV protease enzyme. This is the enzyme that the human immunodeficiency virus largely relies on to multiply and progress. Therefore, in conjugating with boosting drugs, Darunavir treats and prevents human immunodeficiency virus infection and acquired immunodeficiency syndrome.

Prescriptions

• Darunavir is used with Ritonavir and additional HIV drugs for treating HIV infection in adults and children three years of age and older. So, it treats and prevents AIDS, other conditions, and cancers attributable to HIV.

• It is also used for the prevention of infection after needle stick injury. Needle stick injury is known for the penetration of a hypodermic needle or any sharp belongings that were in contact with the blood.

• Used in specific potential exposures, as in occupation and hospital settings.

Drug and Dosage

Route of Administration

Oral

Drug Form and Strength

• Biconvex, colored and film-coated tablets- 400 mg, 600 mg, and 800 mg.

• Oral suspension- 100 mg/mL

Drug Dosage for HIV Infection

Darunavir is used in coadministration with Ritonavir or additional antiretroviral agents. So, doctors generally prescribe these doses.

• Darunavir 800 mg and Ritonavir 100 mg oral tablets once daily with food for treatment-naive people (antiretroviral experienced).

• In another way, Darunavir 600 mg with Ritonavir 100 mg tablets once every 12 hrs with food for treatment-experienced people.

What Are the Precautions and Warnings of the Drug Darunavir?

• Allergy: Darunavir and its component sulpha can precipitate severe and potentially life-threatening allergic skin reactions. The signs include rash, hives, swelling of the face or lips, and trouble breathing. One should seek a doctor or emergency care. One should not retake the medication with a history of allergy, as it would lead to complications.

• Pregnancy: No adequate or appropriate data from studies determine the drug-allied risk in pregnant women. But it is considered safe. However, like all drug therapies, considerations should be taken with Darunavir during pregnancy. So, inform the doctor about the pregnancy or a plan for pregnancy.

• Breastfeeding: The studies validating the use and its risk during breastfeeding are inadequate. But one must be cautious and inform the physician in cases of breastfeeding. So, discontinuing either breastfeeding or the drug is advised since the drug passes through.

• Children: Darunavir is not recommended and advised for infants under three years of age.

For Patients

What Are the Effects of HIV Infection?

Human immunodeficiency virus (HIV) is a virulent virus that affects the body's immune system. It can lead to acquired immunodeficiency syndrome (AIDS) if not treated. The symptoms are based on the type of phase. The condition holds two phases: the primary acute phase and the clinically latent phase called the chronic one. People infected with HIV generally develop flu-like illnesses within a few weeks of virus access. This primary phase presents with limited symptoms which people might fail to notice. But, there is an increased concentration of the virus in the bloodstream. The next stage is the chronic one that lasts for years with or without symptoms in which the people receive antiretroviral treatment. Here, the system and the white blood cells still contain HIV, leading to severe diseases and illnesses.

Symptoms

The most common symptoms of HIV infection include the following.

• Fever.

• Rash.

• Headache.

• Muscle aches.

• Joint pain.

• Weight loss.

• Diarrhea.

• Excessive sweating.

• Cough.

• Swollen lymph nodes.

• Oral yeast infection.

• Pneumonia.

• Shingles infection.

How Does HIV Infection Progress to AIDS?

The symptomatic HIV infection begins when the virus progresses and degrades the healthy immune system. As a result, chronic signs of infection develop. However, most HIV infection does not progress to AIDS since they better ingress to a wide range of antiviral interventions. As a result, the deaths resulting from HIV, including mortality and morbidity, have been significantly reduced.

So, the people receiving appropriate and enlightening treatment get benefits and do not get AIDS. Nevertheless, the untreated ones progress into AIDS in relatively eight years. In these cases, the immune system and the CD4 cells in the blood are targeted and deteriorate. So, people are more likely and prone to opportunistic infections or cancers. At the same time, opportunistic diseases are known for the infection that does not affect people with healthy immune systems but influences HIV people to a greater extent.

Role of Darunavir in HIV and AIDS

Unfortunately, there is no permanent curative for this deadly disease, HIV infection or AIDS. But, certain treatments are prescribed to control HIV infection. These treatment options, specifically antiretroviral therapy, help people live prolonged and more productive lives. HIV causes infection with the help of the HIV protease enzyme and thus deteriorates the CD4 cell levels, invading the immune system. Darunavir is a protease inhibitor that inhibits the enzyme and increases the CD4 cell concentrations. Therefore, the HIV in the system is diminished.

How to Take Darunavir?

Darunavir exists in specific dosages and formulations, though. Therefore, the drug is generally advised to be taken with certain medications that increase the amount and efficacy of Darunavir and additional antiretroviral drugs. The medical healthcare professionals will prescribe the appropriate form and dosage based on age, the severity of the HIV infection, and underlying medical illnesses. Consequently, the drug influences individuals in a contrary fashion. Hence, one should take the drug as per the instructions and directions to attain the full effects yet reduce the risks of side effects. The medication comes with the manufacturer's direction, so read the label conscientiously and ask queries to medical healthcare professionals, if any.

Things to Consider and Inform the Doctor

• One should inform the doctor if one is allergic to Darunavir or sulfa medications since it includes sulfa components. Also, tell if you are allergic to any other ingredients in the prescribed one.

• Also, allergies to other drugs should be informed formerly.

• Convey the doctor about the additional medications, nutritional supplements, and vitamins one takes. So, inform without fail if one takes or plans to take these medications such as Alfuzosin, Dronedarone, Elbasvir, Ergotamine, Dihydroergotamine, Lomitapide, Lovastatin, Lurasidone, Methylergonovine, Midazolam, Pimozide, Sildenafil, Rifampin, Simvastatin, and St.John's Wort. The doctor might consider altering the dose or discontinuation Darunavir.

• Eventually, inform priorly if one is taking the following medications. Anticoagulants (blood thinners), Digoxin, Diuretics, Itraconazole, Ketoconazole, Metoprolol, Timolol, Carvedilol, Betamethasone, Budesonide, and other hypertensives, depression, chemotherapeutic and cardiac-related medications.

• Also, inform the doctor in cases of other HIV medications.

• Hormonal contraceptives and others such as birth control pills, rings, patches, implants, or injections should be informed.

• Also, medications other than the above list must be conveyed to the doctors since Darunavir has a vast range of drug interactions.

• Tell the doctor in case of any medical illnesses or conditions. So inform certainly in the cases of diabetes mellitus, hemophilia, hepatitis, liver cirrhosis, other liver impairments, cytomegalovirus infection, pneumonia, and tuberculosis.

• The doctor should know if one is pregnant, breastfeeding, or has any plans for pregnancy. One should not breastfeed with HIV infection or in Darunavir therapy.

• The drug Darunavir might reduce the efficacy of hormonal contraceptives like birth control pills, patches, and rings. In this case, one can use non-hormonal contraceptive devices like condoms or a diaphragm to prevent pregnancy.

Directions to Take the Darunavir Tablet

• Darunavir tablet is to be taken orally.

• Darunavir tablets are advised to take along with boosting drugs such as Ritonavir or cobicistat. So, take it as directed.

• The medication is generally advised to be taken with food.

• Swallow the capsule as a whole with a glass of water or milk. Do not chew or break them.

• Take Darunavir and its combination drugs around the same time every day.

• Take the doses per the physicians’ directions, such as the number of tablets, amounts, and length of time.

• Do not stop taking the medication without the doctor's consent.

• In addition, do not miss the dose or overdose on them. So, one should complete the drugs as prescribed, though with an improvement.

• Subsequently, call the doctor if there is no improvement, worsening of symptoms, or adverse effects.

Directions to Take Darunavir Oral Suspension

• Shake the Darunavir oral suspension before each use.

• One can use the oral dosing syringe to withdraw the appropriate amount of oral suspension.

• Then, ingest the suspension rightly from that oral disposal syringe.

• Wash and dry utterly after each suspension.

• Also, read the label instructions for precise directions.

Dietetic Consideration

One can follow the routine diet and the classical eating method until the doctor advises on restrictions. However, a well-balanced, healthy diet paves the way for good physical, emotional, and social states. Talk to healthcare professionals about ingesting grapefruit and grape drinks during this medication.

Storage

• Store the Darunavir medications at room temperature, away from heat, moisture, and sunlight.

• So, save them between 20 and 25 degree Celsius.

• Any medication should be stored away from the reach of children.

• Hence, fill them in a safe, tight container that little ones cannot reach. But, of course, this is supposed to be done with caution to safeguard them from drug poisoning.

How to Dispense With Darunavir?

• One should safely dispose of unused or expired medicines in a precise way that the little children, pets, and companions will not address.

• The medication is not meant to be flushed in the toilet, thrown in the community garbage, or poured into the channel.

• The way of disposing of the medication is by approaching the local recycling technique like the talk-balk program.

• Reach out to another safe way of disposal in the community in cases of unavailability of the programs.

What if One Misses the Dose of Darunavir?

If one misses or halts the medication, there is no further improvement. So, take the missed dose right after the thought. In contrast, If it is almost time for the next one, skip the missed dose and proceed with the subsequent dose. Nevertheless, one should not take a double dose to compensate for the missed one.

In Cases of Overdose of Darunavir

Darunavir overdose leads to dangerous altitudes of the drug held in the system. The alarming signs include collapse, seizure, difficulty breathing, and inability to wake. Reach out to the doctor or emergency helpline rightly when one takes excessive medication.

Side Effects of Darunavir

Darunavir is considered safe and effective in conjunction with other drugs. It has certain side effects but is mild and usually resolves with time. If not so, one must talk with the health care professionals.

• Headache.

• Diarrhea.

• Nausea.

• Vomiting.

• Dizziness

• Stomach pain.

• Constipation.

Serious Side Effects and Considerations

The drug Darunavir, an antiretroviral therapy, can result in severe adverse reactions in the system. So, seek professional help soon if the person encounters the following.

• Increased bleeding in hemophilia people. The signs include unusual bleeding from the nose, urine, cough, and gums.

• Skin rashes.

• Signs of diabetes or high blood sugar include excessive urination, increased thirst, weight loss, infections, and poor wound healing.

• Changes or excess in the body fat in specific regions, including breast, upper back, and stomach.

• Changes in cholesterol levels.

• Liver concerns like chronic vomiting, abdominal pain, itching, fever, yellowish discoloration of the skin, and dark-colored urine.

• Changes in the immune system include fever, fatigue, muscle ache, joint pain, rashes, redness, and liver concerns.

Subsequently, one should stop the Darunavir medication and seek medical attention in cases of the following signs.

• Serious allergic reactions- swelling of the throat, face, hives, and trouble breathing.

• Severe skin reactions- blisters, peeling, and rashes.

• Signs of pancreatitis - nausea, vomiting, and severe stomach ache.

For Doctors

Clinical Data of Darunavir

• Generic name: Darunavir.

• Drug class: antiretroviral drug.

• Chemical formula: C27H37N3O7S

• Molar mass: 547.67 g.mol -1

Indication of Darunavir

Darunavir in coadministration with Ritonavir or other antiretroviral drugs is indicated in treating human deficiency virus infection. So, it is widely used in the following ways.

• Children of three years and above with HIV.

• Adults with HIV infection or AIDS.

Associated Conditions

• Human immunodeficiency virus infection Type 1.

Pharmacology of Darunavir

Mechanism of Action

Antiretroviral therapy for HIV infection addresses and targets the HIV-1 protease enzyme in the system. This enzyme is responsible for the production, distribution, and maturation of viral precursor protein in the whole process of infection. These protease inhibitors are markedly known to be effective in suppressing the virus activities and so make allowances for a decline in mortality and morbidity rates. Therefore, HIV protease inhibitor is one of the HAART, highly active antiretroviral therapy, as it serves the purpose in people with HIV.

Darunavir is an HIV protease inhibitor and thus works on inhibiting the virus and preventing HIV replication. Firstly, the drug binds to the HIV protease enzyme and blocks its dimerization and catalytic action. Darunavir can bind to different aspects of enzymes, such as the active site cavity and protease dimer. In addition, it quickly acclimatizes to the enzyme's shape because of its flexibility. Distinctly, the drug stops the cleavage process of HIV-encrypted Gal-Pol proteins in cells formerly affected by HIV. The drug Darunavir is attributable to the efficacy in hostile to the insusceptible variants of HIV due to the contact that Darunavir enhances with active chains of amino acids at the primary chains such as Asp-29 and Asp-30. As a result, immature and non-infectious viral means are developed.

Pharmacodynamics

• Darunavir is an antiretroviral agent that inhibits human immunodeficiency virus protease and blocks replication.

• In cases where Darunavir is administered with Ritonavir as the combination treatment, the Darunavir drug noticeably diminishes the viral burden, increasing the CD4 cell levels.

• Therefore, the mortality and morbidity views are significantly reduced.

Absorption

• The outright bioavailability of a single dose of Darunavir is 37%.

• The bioavailability of the combination of Darunavir and 100 mg of Ritonavir is 82%.

• After oral administration, the peak plasma concentration Tmax is attained in about 2.5 to 4 hours.

• Exposure to Darunavir is significantly increased by eleven times in boosted people compared to unboosted ones.

Distribution

• The volume of distribution of the combination antiretroviral treatment of Darunavir and Ritonavir is about 161.0 to 264.9 L, according to a study of volunteers.

• A further study on Darunavir's pharmacokinetics showed the distribution volume as 220 L.

• The plasma protein bound of Darunavir is relatively 95%.

• The drug Darunavir chiefly binds to plasma protein, specifically alpha one acid glycoprotein (AAG).

Metabolism

• Darunavir is well-extensively oxidized and metabolized using CPY3A, a hepatic cytochrome enzyme.

• It is also well metabolized in unboosted people through isobutyl aliphatic hydroxylation, carbamate hydrolysis, glucuronidation, and benzylic aromatic hydroxylation.

Elimination

• The single dose of Darunavir administration in conjugation with Ritonavir is thus eliminated and traced in the urine 14% and feces 80%.

Half-life and Clearance

• The terminal half-life of combination antiretroviral treatment, including Darunavir and Ritonavir, is relatively 15 hours.

• The Darunavir presents a low clearance rate. Following intravenous administration, the renal clearance rate of Darunavir alone is 32.8 L/h.

• And the clearance of a combination of Darunavir and Ritonavir twice daily is about 5.9 L/h.

Contraindications of Darunavir

The coadministration of Darunavir with Ritonavir is contraindicated with other drugs highly dependent on CPY3A for renal clearance. Subsequently, the particular combination is contraindicated with drugs exhibiting increased plasma concentrations and influencing severe life-threatening complications.

The followings are the contraindicated drugs and other affiliated drugs that diminish the efficacy of Darunavir.

• Alpha-1 adrenoceptor antagonist- Alfuzosin.

• Anti-gout drugs such as Colchicine in hepatic and renal impairments.

• Antipsychotic drugs such as Pimozide and Lurasidone.

• Rifampin is an antimycobacterial drug.

• Ergot derivatives like Ergotamine, Methyergonavine, and Dihydroergotamine.

• Cardiac means such as Ivabradine, Dronedarone, and Ranolazine.

• Herbal supplement- St.John’s wort.

• Cisapride.

• Antivirals for hepatitis C- Elbasvir or Grazoprevir.

• Lipid-modifying agents such as Lovastatin, Lomitapide, and Simvastatin.

• Naloxegol is an opioid antagonist.

• Orally administered sedatives like Triazolam and midazolam.

• PDE-5 inhibitor- sildenafil prescribed for pulmonary arterial hypertension.

Adverse Effects

The drug Darunavir increases the blood's total cholesterol and triglyceride concentrations. Subsequently, it shows side effects such as nausea, vomiting, anorexia, diarrhea, fatigue, and rash.

The drug also exhibits the following severe yet adverse reactions.

• Hepatic disorders- Hepatotoxicity and acute hepatitis.

• Asthenia, an administration site reaction.

• Gastrointestinal disorders like dyspepsia, flatulence, and acute pancreatitis.

• Diabetes mellitus or hyperglycemia.

• Body fat redistribution.

• Musculoskeletal and connective tissue conditions, particularly osteonecrosis and myalgia.

• Immune system concerns, namely hypersensitivity reaction and hyperImmune reconstitution syndrome.

• Skin and subcutaneous tissue disorders, namely pruritus, urticaria, Stevens-Johnson syndrome, and angioedema.

• Hemophilia.

• Distorted dreams.

Essential Considerations for Darunavir

• Significance of Coadministration with Ritonavir - Darunavir must be co-administered or used in conjugation with Ritonavir to attain the desirable antiviral effect. This is because Darunavir highly depends on CYP3A4 for metabolization, while Ritonavir is a significant CYP3A4 inhibitor.

• Hepatic Impairments - Studies report drug-induced hepatobiliary disorders, particularly cytolytic hepatitis and acute hepatitis. The studies prevail that the drug increases the risk of liver concerns and acute hepatic events in people with pre-existing hepatic impairments. Therefore, appropriate laboratory monitoring should be performed before and during the drug treatment. Moreover, the number of AST and ALT monitorings should be inflated in people with liver cirrhosis, chronic hepatitis, and pretreatment of transaminase. Consider the interruption or discontinuation of Darunavir treatment if the symptoms exhibit deteriorating liver dysfunction.

• Sulfa Allergy - Darunavir contains a sulfonamide component, so the drug must be cautiously prescribed. Nevertheless, the studies reveal similar patterns of rash and allergy in both sulfonamide-allergic and non-allergic people.

• Skin Concerns - The clinical trials demonstrate that the drug Darunavir might indulge in severe skin reactions in association with fever and increased transaminase. In addition, it includes stevens-johnson syndrome but rarely. Therefore, discontinuation should be considered if the person develops the most severe skin reaction, rashes accompanying fever, malaise, myalgia, blisters, hepatitis, oral lesions, conjunctivitis, and eosinophilia. Nevertheless, the studies and evidence show that these skin reactions are considered due to the drug interactions of Darunavir with Ritonavir and raltegravir.

• Hyperglycemia - The protease inhibitor drug therapy resulted in the onset of diabetes mellitus in new people and the exacerbation of preliminary diabetes mellitus with hyperglycemia. While some showed diabetic ketoacidosis, insulin drug modifications or oral hypoglycemic drugs are thus recommended in several cases.

• Fat Redistribution - The reports presented the fat redistribution or accumulation of fat in the system. So, antiretroviral therapy showed dorsocervical fat enlargement, central obesity, facial wasting, peripheral wasting, and breast enlargement. But, the studies have yet to determine the relationships.

• People with Hemophilia - When treated with protease inhibitors, the reports reveal increased bleeding risks, skin hematomas, and hemarthrosis in people with hemophilia type A and B. Hence the consideration includes the recommendation of factor VIII. In addition, the protease inhibitor therapy is continued or reintroduced.

Possible Drug Interactions of Darunavir

Darunavir is known to interact with around 456 drugs, of which 102 show major, 334 moderate, and 20 show minor interactions. Moreover, several drugs can result in severe adverse reactions when interacting with Darunavir. A few interactions are described below.

• Interaction with Benzodiazepines - The metabolism and efficacy of benzodiazepines get diminished when combined with Darunavir.

• Interaction with Alfuzosin - The combination of Darunavir and Alfuzosin increases the risk and severity of hypotension.

• Interaction with Aluminum Hydroxide - Aluminum hydroxide tends to cause a diminished absorption of Darunavir when interacted with. This results in a decreased serum concentration and potential efficacy of Darunavir.

• Interaction with St.John's Wort - Darunavir’s serum concentration might decrease when combined with an herbal supplement called St.John wort.

• Interaction with Verapamil - The combination of Darunavir and Verapamil increases the overall serum concentration of Verapamil.

How Far Have Clinical Trials Proven the Effects of Darunavir?

A clinical-trial-based study was conducted to validate Darunavir's safety and efficacy in treating human immunodeficiency virus infection and acquired immunodeficiency syndrome. The clinical trial was intervention based and randomized, with 120 participants. The Hiv infected patients were given Darunavir and Ritonavir at 800 and 100 mg, respectively. The dosage is given as monotherapy based on a switch-maintenance technique for patients receiving antiretroviral therapy. Follow-ups are done after 24 weeks to determine the viral load, efficacy, and adverse effects.

Results

Darunavir therapy reduced the viral load when administered once daily in treatment-naive adults and twice daily in treatment-experienced adults. Darunavir is generally well-tolerated but showed quite gastrointestinal disturbances and lipid abnormalities. Therefore, the results are incorporated based on the fact that Darunavir is a favorable and useful option for the antiretroviral regimen in adults and children with HIV infection.