Cabotegravir - HIV/AIDS

What Is Cabotegravir?

Cabotegravir is a medicine used to treat HIV (human immunodeficiency virus) or AIDS (acquired immunodeficiency syndrome). It is available as tablets, as an injection into the muscle, and as a combined injection with Rilpivirine (another HIV medicine).

In 2021, the FDA (Food and Drug Administration) approved Cabotegravir for PrEP (pre-exposure prophylaxis) to help protect people at risk of getting HIV. Cabotegravir for HIV prevention is now considered a reliable option.

What Is the Clinical Use of Cabotegravir?

Cabotegravir is a medicine used to treat HIV (a type of virus that weakens the body’s immune system). It can be used by adults as their only treatment. It can also replace their current HIV treatment if the virus is already under control (called virologically suppressed, meaning the virus is very low in the body). This switch can be done only if the person has never had treatment failure (treatment not working) and has no resistance (when the virus stops responding) to Cabotegravir or Rilpivirine.

What Are the Dosage Forms And Strengths?

Cabotegravir appears as a white to light pink, free-flowing, extended-release injectable suspension (meaning it releases the medicine slowly in the body).

The single-dose vial of Rilpivirine appears as a white to off-white, extended-release injectable suspension. Both of them are co-packaged as a 400-milligram (mg)/600-mg kit.

• Injection: 400 mg/2 mL (200 mg/mL) of Cabotegravir suspension in a single-dose vial.

• Injection: 600 mg/2 mL (300 mg/mL) of Rilpivirine suspension in a single-dose vial, Cabotegravir 600 mg/900 mg kit.

• Injection: 600 mg/3 mL (200 mg/mL) of Cabotegravir suspension in a single-dose vial.

• Injection: 900 mg/3 mL (300 mg/mL) of Rilpivirine suspension in a single-dose vial.

What Are the Warnings and Precautions?

Hypersensitivity reactions:

Some people who took medicines containing Rilpivirine had allergic reactions. Some people had fever, skin rashes, and problems in organs like the liver (shown by high liver test values).

Severe allergic reactions have also happened with other integrase inhibitors (a type of HIV medicine), so they can also happen with Cabotegravir. If an allergic reaction is suspected, Cabotegravir must be stopped immediately.

Post-Injection reactions

In some studies, a few people had serious reactions within minutes after getting the Rilpivirine injection. These included:

• Dyspnea (trouble breathing).

• Agitation (feeling very restless).

• Flushing (face becoming red and warm).

• Sweating.

• Abdominal cramps (stomach pain).

• Oral numbness (mouth feeling numb).

• Changes in blood pressure.

These reactions happened in less than 1% of people and usually went away within a few minutes. They may have happened because the medicine accidentally entered a vein (partial intravenous administration). To prevent this, the injection must be prepared and given correctly.Patients should be watched closely after the injection. If someone reacts, they should be monitored and treated as needed.

Hepatotoxicity

Some people taking Cabotegravir or Rilpivirine developed liver problems, even if they never had liver disease before. People who already have liver issues or very high liver enzymes before treatment may have a higher risk of worsening. Doctors should check liver tests regularly. If liver damage is suspected, Cabotegravir should be stopped.

Depressive disorders

Some people taking Cabotegravir have reported:

• Depressed mood (feeling very sad).

• Depression.

• Dysphoria (feeling uneasy or unhappy).

• Negative thoughts.

• Suicidal thoughts.

Patients with these symptoms should be checked to see if Cabotegravir is causing them. The doctor will decide whether the benefits of the medicine are greater than the risks.

For Patients

How Effective Is Cabotegravir?

Studies show that Cabotegravir, as a long-acting HIV treatment, works very well to prevent HIV. In a study, Cabotegravir reduced the chance of getting HIV much more than the usual prevention methods. It was found to be 66 % more effective than the current standard care.

Things to inform the doctor before taking cabotegravir:

Inform the doctor in case of any of the following conditions:

• Do not use Cabotegravir if you are allergic to it or any of its ingredients, or if you are taking certain medicines such as Carbamazepine, Oxcarbazepine, Phenytoin, Phenobarbital (used for epilepsy), or Rifampicin and Rifapentine (used for infections).

• Tell your doctor if you have liver problems or have had hepatitis B or C, as they may need to check how severe your liver condition is before giving Cabotegravir.

• Vocabria is not recommended during pregnancy unless the doctor decides that the benefits are greater than the possible risks to the baby.

• Talk to your doctor beforehand if you are planning to get pregnant. Breastfeeding is not advised for women with HIV because HIV can pass to the baby through breast milk.

What Are the Side Effects of Cabotegravir?

• Headache.

• Pain, discomfort, redness, itching, swelling, warmth, bruising, numbness, a small lump, slight bleeding, or rarely an abscess at the injection site.

• Feeling hot or feverish (pyrexia) within one week after the injection.

• Mood changes.

• Difficulty sleeping.

• Giddiness (feeling dizzy).

• Weakness.

Report to a doctor immediately if you experience:

• Allergic reactions such as skin rash, muscle aches, or extreme tiredness

• Signs of infection, such as muscle weakness, muscle pain, palpitations (fast or uneven heartbeat), or joint pain

What Should Be Done If a Dose Is Missed?

Planned missed doses:

If someone knows they will miss an injection by more than seven days, the doctor may prescribe daily oral Cabotegravir for up to two months to replace one missed injection. Take the medicine exactly as the doctor advises.

Unplanned missed dose:

If an injection is missed unexpectedly by more than seven days and no oral doses were taken, the doctor will check the patient to see if it is safe to continue injection treatment. Follow the doctor’s instructions.

What Should Be Done to Treat Cabotegravir Overdose?

In case of an overdose of Cabotegravir, medical attention should be sought immediately. The individual should go to the nearest emergency department or contact their healthcare provider as soon as possible.

Cabotegravir is a prescription medication, and it should not be taken without the guidance of a healthcare professional. Self-medication with Cabotegravir can be dangerous and may cause serious harm to the individual.

While using the medication, the physician must monitor the patient on a regular basis. It includes investigations like routine blood tests to check the effectiveness of medication and to analyze adverse effects.

For Doctors

Indication:

• Cabotegravir is used to prevent sexually transmitted HIV-1 in adults and adolescents who weigh at least 77 pounds.

• A combination of Cabotegravir and Rilpivirine is used as a full HIV-1 treatment for adults and adolescents who weigh at least 77 pounds, have stable viral control, no past treatment failure, and no known resistance to either medicine.

Dosing:

Pre-exposure Prophylaxis (PrEP) of sexually transmitted HIV:

The doctor may first check how well the patient tolerates Cabotegravir PrEP using an optional "lead-in" phase.

With an oral lead-in:

• Take 30 mg of Cabotegravir by mouth every day for at least 28 days.

• Then receive a 600 mg injection in the muscle at months 2 and 3.

• After that, receive a 600 mg injection every two months.

Without an oral lead-in:

• Receive injections at months one and two.

• Then receive a 600 mg injection at month four and continue every two months after that.

Dosing Considerations:

Screening -

• For individuals receiving Cabotegravir for HIV-1 PrEP (pre-exposure prophylaxis), the FDA label recommends HIV-1 screening prior to initiation of Cabotegravir therapy and at least every three months during treatment.

• The screening should include testing for acute HIV-1 infection before and during treatment. The label also recommends that individuals should not start Cabotegravir for HIV-1 PrEP if they have indications of acute HIV-1 infection or if HIV-1 antibody test results are positive.

Adherence -

• Healthcare providers should select patients who are ready to follow the required injection and testing schedule.

• Patients should be educated on the importance of keeping all scheduled dosing appointments.

• This helps reduce the risk of getting HIV-1 and the development of drug resistance before starting Cabotegravir treatment.

Pharmacology:

Mechanism of action:

Cabotegravir is an integrase strand transfer inhibitor (INSTI) (a type of HIV medicine that blocks an enzyme called integrase, which the virus needs to multiply). It works by inhibiting the action of the integrase enzyme (stops HIV from copying itself in the body), which is required for the proliferation (growth and spread) of HIV.

Pharmacodynamics:

Cabotegravir blocks HIV integrase, lowering the virus's replication. It has a sustained effect, as the oral tablet is taken daily, and the intramuscular suspension is given monthly. Patients should be advised about the potential hazards of hypersensitivity, hepatotoxicity, and mood changes.

Absorption:

Cabotegravir is absorbed after oral administration and intramuscular injection.

For the oral tablet, the maximum concentration in the blood is reached approximately two to four hours after administration.

The absolute bioavailability of Cabotegravir after oral administration is about 65 percent. Food has no significant effect on the absorption of Cabotegravir. For the intramuscular suspension, the maximum concentration in the blood is reached approximately three to four days after injection.

Distribution:

Cabotegravir is highly protein-bound (greater than 99 percent) to plasma proteins, including albumin and alpha-1 acid glycoprotein. After intravenous administration, the drug's volume of distribution is approximately 6.05 gallons. The drug penetrates the blood-brain barrier to some extent.

Metabolism:

Cabotegravir is mainly metabolized by UGT1A1 and CYP3A4 enzymes in the liver (these are liver proteins that help process the drug).

• Major pathway: Glucuronidation (the liver adds a chemical group called glucuronic acid) converts Cabotegravir into Cabotegravir glucuronide, which is inactive (no longer works as medicine).

• Minor pathway: Oxidative metabolism by CYP3A4 forms a pharmacologically active metabolite (a substance that still works to fight HIV).

Excretion:

The elimination half-life of Cabotegravir is approximately 40 to 50 hours after oral administration and 54 days after intramuscular injection. Cabotegravir and its metabolites are mainly excreted in the feces (70 percent) and, to a lesser extent, in the urine (30 percent).

Warnings and Precautions:

• Immunologic - The use of Cabotegravir and other integrase inhibitors may lead to serious hypersensitivity reactions, such as rash, fever, fatigue, or difficulty breathing. If any of these symptoms occur, the medication should be stopped immediately. Additionally, residual amounts of injectable Cabotegravir may still be present in the body for a year or more after stopping treatment.

• Hepatic - Patients with and without liver disease or risk factors have reported liver damage due to Cabotegravir. Those with existing liver issues or high levels of transaminases before treatment are at higher risk of worsening liver problems. Monitoring is recommended for these patients, and treatment should be discontinued if there are indications of liver damage.

• Psychiatric - The medication also causes depressive disorders, such as mood changes. It is essential to consider the advantages and dangers of continuing the medication.

• Others - To avoid adverse effects such as loss of virologic response and possible development of viral resistance, it is important to review any medications taken with Cabotegravir before and during treatment, as there may be known or potentially significant drug interactions.

Contraindications:

Cabotegravir is contraindicated in the following conditions:

• Patients with a history of hypersensitivity to Cabotegravir or its components.

• Along with Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin, Rifampin, and Rifapentine.

Drug interactions:

• Concomitant use with other antiretroviral medicines - Since Cabotegravir is a complete regimen, administering it with other antiretroviral medications for treating HIV-1 infection is not recommended.

• Use of other antiretroviral drugs after discontinuation of cabotegravir - The residual quantity of Cabotegravir and Rilpivirine may persist in the systemic circulation for a year or more. These residual concentrations usually do not affect the exposures of antiretroviral drugs that are administered after discontinuation of Cabotegravir.

• Potential for other drugs to affect cabotegravir - Cabotegravir is mainly metabolized by the UGT1A1 gene (a liver enzyme that helps break down the drug), with some contribution from the UGT1A9 gene (another liver enzyme that also helps process the drug). Strong inducers of UGT1A1 or UGT1A9 (drugs that increase the activity of these liver enzymes) can lower Cabotegravir levels in the blood (less medicine available to work against HIV) and may cause loss of virologic response (the virus may start replicating again because the drug is less effective). Therefore, taking Cabotegravir with these drugs is contraindicated.

Other specifications:

• Pregnancy - Insufficient human data are available on the use of Cabotegravir during pregnancy to evaluate the risk of birth anomalies (birth defects) and miscarriage properly. Cabotegravir and Rilpivirine may remain in the bloodstream for 12 months or more after stopping injections. Therefore, the possibility of exposing a fetus during pregnancy should be taken into account.

• Lactation - The Centers for Disease Control and Prevention (CDC) recommends that HIV infected mothers not breastfeed their newborns to prevent the danger of postnatal transmission of HIV-1. It is unknown if the components of Cabotegravir exist in human breast milk, affect human milk generation, or impact infants who are breastfed. When Cabotegravir was administered to lactating rats, it was present in the milk.

• Pediatric use - The safety and efficacy of Cabotegravir have not been evaluated yet in pediatric patients.

• Geriatric use - Clinical trials of Cabotegravir did not have sufficient subjects aged 65 years and above to conclude whether older people respond differently from younger people. In general, the administration of Cabotegravir in elderly patients should be practiced with caution, especially for those with an increased frequency of decreased renal, hepatic, or cardiac function and other diseases or drug therapy.

• Renal impairment - Studies with oral Cabotegravir and oral Rilpivirine have shown that no dose adjustment is needed for mild or moderate kidney problems (the usual dose is safe for patients with slightly or moderately reduced kidney function). However, for patients with severe kidney problems or end-stage renal disease (very poor kidney function or kidneys that are nearly failing), closer monitoring is needed.

• Hepatic impairment - For patients with mild or moderate liver problems (slightly or moderately reduced liver function), Cabotegravir and oral Rilpivirine show that no dose adjustment is required (the usual dose is safe). For patients with severe liver problems (seriously reduced liver function), the effect of Cabotegravir or Rilpivirine on the body is not fully known. Doctors should monitor liver function carefully (regular blood tests may be needed to check for liver damage or side effects).