REZOLSTA

What Is REZOLSTA and What Is It Used For?

REZOLSTA is a fixed-dose combination tablet containing two active substances: darunavir (675 mg), an HIV protease inhibitor, and cobicistat (150 mg), a pharmacokinetic enhancer (booster). It is used as part of combination antiretroviral therapy (cART) to treat HIV-1 infection in children aged 6 years and older weighing at least 25 kg but less than 40 kg.

Darunavir belongs to a class of antiretroviral medicines called protease inhibitors (PIs). During HIV replication, the virus produces long polyprotein chains that must be cleaved by the HIV-1 protease enzyme into smaller functional proteins for the virus to mature and become infectious. Darunavir selectively binds to the active site of the HIV-1 protease, preventing this cleavage. As a result, immature, non-infectious viral particles are produced, effectively blocking viral replication and reducing the amount of HIV in the blood (viral load).

Cobicistat is not an antiviral agent itself. It acts as a pharmacokinetic enhancer or “booster” by inhibiting the cytochrome P450 3A (CYP3A) enzyme system in the liver and gut. Since darunavir is extensively metabolised by CYP3A, co-administration with cobicistat significantly increases darunavir’s systemic exposure (blood levels), allowing for effective therapeutic concentrations with a single daily dose. This boosting mechanism is functionally similar to the role of ritonavir in older protease inhibitor regimens, but cobicistat has the advantage of having no intrinsic anti-HIV activity, which means it does not contribute to drug resistance.

By reducing the viral load to very low or undetectable levels, REZOLSTA treatment allows the immune system – specifically the CD4+ T-lymphocyte count – to recover. This immune reconstitution reduces the risk of developing opportunistic infections and other HIV-associated diseases. However, it is critical to understand that REZOLSTA is not a cure for HIV. The virus remains in the body in latent reservoirs, and discontinuation of treatment will lead to viral rebound.

REZOLSTA must always be used in combination with other antiretroviral medicines as part of a complete treatment regimen. Your prescribing physician will determine the optimal combination based on your treatment history, resistance testing results, and current treatment guidelines from organisations such as the European AIDS Clinical Society (EACS), the US Department of Health and Human Services (DHHS), and the World Health Organization (WHO).

What Should You Know Before Taking REZOLSTA?

Before starting REZOLSTA, inform your doctor about all medical conditions, especially liver disease (including hepatitis B or C), kidney problems, diabetes, and haemophilia. REZOLSTA is contraindicated in patients with severe liver disease and must never be combined with numerous medications due to serious drug interactions.

Contraindications

You must not take REZOLSTA if any of the following apply to you:

• Allergy to darunavir, cobicistat, or any excipient – symptoms of a severe allergic reaction may include rash, swelling of the face or throat, and difficulty breathing
• Severe liver disease – patients with severe hepatic impairment (Child-Pugh Class C) must not use REZOLSTA. If you are unsure about the severity of your liver condition, your doctor may order additional tests before deciding whether REZOLSTA is safe for you
• Co-administration with contraindicated medicines – REZOLSTA must not be taken with numerous medications that interact dangerously through CYP3A pathways (see the drug interactions section below for the complete list)

Warnings and Precautions

Talk to your doctor, pharmacist, or nurse before taking REZOLSTA if you have or have had any of the following conditions:

• Liver problems, including hepatitis B or C co-infection – REZOLSTA may worsen liver function. Your doctor will order regular blood tests to monitor liver enzymes, and more frequent monitoring is required in patients with chronic hepatitis
• Kidney disease – your doctor will carefully evaluate whether REZOLSTA is appropriate for you, as cobicistat can affect renal tubular function and may cause small increases in serum creatinine
• Diabetes – protease inhibitors, including darunavir, can increase blood sugar levels. Your doctor may need to adjust your diabetes medications and will monitor your glucose levels more closely
• Haemophilia – patients with haemophilia type A or B may experience increased bleeding when taking protease inhibitors. Additional coagulation factor may be needed
• Sulfonamide allergy – darunavir has a sulfonamide chemical moiety, and there is theoretical potential for cross-reactivity in patients with a history of sulfonamide allergy. Inform your doctor if you have ever had allergic reactions to sulfonamide-containing medicines

Immune Reconstitution Inflammatory Syndrome (IRIS)

When HIV treatment is started, the recovering immune system may mount an inflammatory response against previously latent or subclinical infections that were present before treatment began. This phenomenon is known as immune reconstitution inflammatory syndrome (IRIS). Symptoms can include fever, swollen lymph nodes, and worsening of pre-existing infections. IRIS typically occurs within the first few weeks to months of antiretroviral therapy initiation.

In addition to opportunistic infections, autoimmune disorders (conditions where the immune system attacks healthy body tissue) may also occur after starting HIV treatment. Autoimmune disorders can appear several months after treatment initiation. If you notice any symptoms of infection, or other symptoms such as muscle weakness beginning in the hands or feet, palpitations, tremor, or hyperactivity, inform your doctor immediately so that appropriate treatment can be provided.

Bone Health

Some patients receiving combination antiretroviral therapy may develop a bone condition called osteonecrosis (death of bone tissue due to loss of blood supply). Risk factors include long-term HIV treatment, severe immunodeficiency, obesity, and concurrent use of alcohol or corticosteroids. Signs of osteonecrosis include stiff and aching joints (especially in the hip, knee, and shoulder) and difficulty moving. Report any such symptoms to your doctor promptly.

Pregnancy and Breastfeeding

Inform your doctor immediately if you are pregnant or planning to become pregnant. Pregnant women should not take REZOLSTA. Your doctor will discuss alternative antiretroviral regimens that have a better-established safety profile during pregnancy.

Breastfeeding is not recommended for women taking REZOLSTA, for two important reasons: first, the active substances may pass into breast milk and cause side effects in the infant; second, HIV can be transmitted to the child through breast milk. The WHO and all major HIV treatment guidelines recommend that women living with HIV should not breastfeed if safe alternatives (formula feeding) are available.

Driving and Operating Machinery

REZOLSTA may cause dizziness in some patients. If you experience dizziness after taking REZOLSTA, do not drive or operate machinery until the symptoms have resolved.

How Does REZOLSTA Interact with Other Drugs?

REZOLSTA has extensive and clinically significant drug interactions because cobicistat is a potent inhibitor of CYP3A, and darunavir is both a substrate and inhibitor of CYP3A. Many commonly used medications are contraindicated or require dose adjustments when used with REZOLSTA. Always inform your doctor about all medicines you take, including prescription drugs, over-the-counter medicines, herbal supplements, and recreational drugs.

The combination of darunavir and cobicistat in REZOLSTA potently inhibits the CYP3A enzyme system. This means that drugs metabolised by CYP3A can accumulate to dangerously high levels in the body, leading to severe or life-threatening adverse effects. Conversely, drugs that induce CYP3A (such as rifampicin or St. John’s wort) can dramatically reduce darunavir levels, causing treatment failure and potential development of HIV drug resistance.

REZOLSTA must not be used with another antiretroviral medicine that contains a pharmacokinetic enhancer (booster) or with another antiretroviral that requires boosting. In some cases, the dosage of co-administered medicines may need to be adjusted. Always follow your doctor’s instructions carefully regarding which medicines can be safely combined with REZOLSTA.

Contraindicated Combinations

The following medicines must never be taken together with REZOLSTA due to the risk of serious or life-threatening adverse effects:

Interactions Requiring Dose Adjustment or Monitoring

The following medicines may require dose adjustments or additional monitoring when used concomitantly with REZOLSTA. Your doctor will determine the appropriate approach:

• Cardiovascular drugs (amlodipine, diltiazem, felodipine, nifedipine, verapamil, metoprolol, carvedilol, digoxin) – effects may be increased; dose reduction and monitoring may be required
• Anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban, warfarin) – bleeding risk may change; dose adjustment and INR/anti-Xa monitoring recommended
• Statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin, pitavastatin) – use lowest possible dose and monitor for signs of muscle toxicity (myopathy)
• Immunosuppressants (ciclosporin, tacrolimus, sirolimus, everolimus) – plasma levels may be significantly increased; therapeutic drug monitoring is essential
• Corticosteroids (budesonide, fluticasone, betamethasone, dexamethasone, prednisone) – risk of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression; use alternatives when possible
• Hormonal contraceptives – REZOLSTA may decrease the effectiveness of oestrogen-based contraceptives; alternative or additional non-hormonal contraceptive methods are recommended
• Opioid substitution therapy (methadone, buprenorphine/naloxone) – clinical monitoring recommended; dose adjustment may be needed
• PDE5 inhibitors for erectile dysfunction (sildenafil, tadalafil, vardenafil) – start with the lowest dose and do not exceed recommended maximum doses. Note: sildenafil for pulmonary arterial hypertension is contraindicated
• Antidepressants (sertraline, paroxetine, amitriptylin, trazodone) – monitor for increased antidepressant effects and adjust dose as needed
• Antimalarials (artemether/lumefantrine) – clinical and ECG monitoring advised
• Cancer medicines (dasatinib, nilotinib, vincristine, vinblastine, irinotecan) – increased toxicity risk; specialist oncology supervision required
• Antifungals (itraconazole, voriconazole, posaconazole) – monitor for increased or decreased antifungal or antiretroviral effects
• Antibiotics (clarithromycin, rifabutin) – dose adjustments may be needed for both medicines
• Sedatives (diazepam, zolpidem, injected midazolam) – monitor for excessive sedation; use the lowest effective dose
• Metformin – clinical monitoring of diabetic control recommended, as cobicistat may affect metformin levels
• Opioid analgesics (fentanyl, oxycodone, tramadol) – respiratory depression risk; careful dose titration required

What Is the Correct Dosage of REZOLSTA?

Always take REZOLSTA exactly as prescribed by your doctor. The 675 mg/150 mg tablet is specifically formulated for children aged 6 years and older weighing 25 kg to under 40 kg. REZOLSTA must be taken once daily with food – a meal or substantial snack should be eaten within 30 minutes before taking the tablet.

Children (6 years and older, 25 kg to <40 kg)

Adolescents and Adults (40 kg and above)

How to Take REZOLSTA

Follow these essential guidelines every time you take REZOLSTA:

• Always take with food – REZOLSTA does not work properly without food. Eat a meal or a substantial snack within 30 minutes before taking your tablet. The type of food does not matter
• Swallow the tablet whole with water or milk. If you have difficulty swallowing, the scored tablet can be split in half by hand – but take both halves immediately
• Take at the same time each day for consistent blood levels
• Take your other HIV medicines exactly as recommended by your doctor

Missed Dose

If you miss a dose of REZOLSTA:

• Within 12 hours: Take the missed dose immediately with food
• More than 12 hours late: Skip the missed dose and take your next dose at the usual time
• Never take a double dose to make up for a forgotten dose

If You Vomit After Taking REZOLSTA

If you vomit within 4 hours of taking your dose, take another REZOLSTA tablet with food as soon as possible. If you vomit more than 4 hours after taking the dose, you do not need to take an additional dose until your next scheduled time. Contact your doctor if you are unsure what to do.

Overdose

If you have taken more REZOLSTA than prescribed, contact your doctor, pharmacist, or nurse immediately, or go to the nearest emergency department. There is no specific antidote for darunavir/cobicistat overdose. Treatment is supportive, including monitoring of vital signs and clinical status.

What Are the Side Effects of REZOLSTA?

Like all medicines, REZOLSTA can cause side effects, although not everyone experiences them. The most common side effects are headache, diarrhoea, and nausea. Serious but less common side effects include liver problems, severe skin reactions, pancreatitis, and diabetes. During HIV treatment, weight gain and changes in blood lipids and glucose may also occur.

As with all antiretroviral therapy, patients should be aware that HIV treatment is associated with changes in body composition, including weight gain and alterations in blood lipid (cholesterol and triglyceride) and glucose levels. These metabolic changes are partly related to the disease control and restoration of health, and partly linked to the antiretroviral medicines themselves. Your doctor will perform regular blood tests to monitor for these changes.

Serious Side Effects

Seek medical attention immediately if you experience any of the following:

• Liver problems – signs include yellowing of the skin or whites of the eyes (jaundice), dark (tea-coloured) urine, pale stools, nausea, vomiting, loss of appetite, or pain on the right side under the ribs. Liver problems can occasionally be severe, particularly in patients with pre-existing hepatitis B or C co-infection
• Severe skin reactions – including rash with blistering and peeling skin (Stevens-Johnson syndrome, toxic epidermal necrolysis), or rash accompanied by fever, fatigue, facial or lymph node swelling, and organ involvement (DRESS syndrome)
• Pancreatitis (inflammation of the pancreas) – severe upper abdominal pain radiating to the back, nausea, and vomiting

Side Effects by Frequency

Frequency not known: Skin rash that may become severe or potentially life-threatening, including widespread blistering and peeling of the skin, and red rash covered with small pus-filled bumps that can spread over the body (sometimes with fever).

Class Effects of Protease Inhibitors

Certain side effects are typical for all HIV medicines in the protease inhibitor class. These include muscle pain, tenderness, or weakness. In rare cases, these muscle-related side effects have been severe. Patients should report any unexplained muscle symptoms to their doctor.

How Should You Store REZOLSTA?

Store REZOLSTA out of the sight and reach of children. REZOLSTA does not require any special storage conditions. Once the bottle is opened, the tablets must be used within 8 weeks.

Follow these storage guidelines to ensure your medicine remains effective:

• Keep out of the sight and reach of children – the bottle has a child-resistant cap. To open, push down on the plastic cap while turning it counter-clockwise
• Check the expiry date – do not use REZOLSTA after the expiry date printed on the carton and bottle (after “EXP”). The expiry date refers to the last day of that month
• Use within 8 weeks of opening – once you first open the bottle, the tablets should be used within 8 weeks
• No special storage conditions required – REZOLSTA can be stored at room temperature
• Proper disposal – do not throw unused medicine in household waste or down the drain. Ask your pharmacist how to dispose of medicines you no longer use, to help protect the environment

What Does REZOLSTA Contain?

Each REZOLSTA 675 mg/150 mg film-coated tablet contains 675 mg of darunavir (as ethanolate) and 150 mg of cobicistat. The tablet is green to dark green, oval, film-coated, with a score line, debossed with “675” on one side and “TG” on the other.

Active Substances

• Darunavir 675 mg (as darunavir ethanolate) – the HIV protease inhibitor
• Cobicistat 150 mg – the pharmacokinetic enhancer

Other Ingredients (Excipients)

Tablet core: colloidal silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

Film coating: yellow iron oxide (E 172), black iron oxide (E 172), polyethylene glycol (macrogol), polyvinyl alcohol – partially hydrolysed, talc, and titanium dioxide (E 171).

Appearance and Packaging

REZOLSTA 675 mg/150 mg tablets are green to dark green, oval, film-coated tablets with a score line, debossed with “675” on one side and “TG” on the other. They are supplied in a plastic bottle containing 30 tablets with a child-resistant cap.