Cabotegravir - HIV/AIDS

Overview

Cabotegravir is an antiretroviral medication used for the treatment of HIV (human immunodeficiency virus) or AIDS (acquired immunodeficiency syndrome). The medication is available in the form of tablets, as an intramuscular injection, and in an injectable combination with Rilpivirine. In December 2021, the United States Food and Drug Administration (FDA) approved Cabotegravir for pre-exposure prophylaxis (PrEP) in at-risk people.

What Is the Clinical Use of Cabotegravir?

Cabotegravir is indicated as a complete regimen for treating human immunodeficiency virus type-1 (HIV-1) infection in adults and to replace the antiretroviral regimen in patients who are virologically suppressed under a stable antiretroviral regimen and have no history of treatment failure or any known or suspected resistance to either Cabotegravir or Rilpivirine.

What Are the Dosage Forms And Strengths?

Cabotegravir appears as a white to light pink, free-flowing extended-release injectable suspension. 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/600-milligram kit.

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

• Injection: 600 milligrams/2 milliliters (300 milligrams/milliliters) of Rilpivirine suspension in single-dose vial Cabotegravir 600-milligrams/900-milligrams kit.

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

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

What Are the Warnings and Precautions?

• Hypersensitivity Reactions- Cases of hypersensitivity reactions have been documented during postmarketing experiences with Rilpivirine-containing regimens. Reactions include cases of drug reactions with eosinophilia and systemic symptoms (DRESS). While some skin reactions were accompanied by symptoms such as fever, and skin reactions with organ dysfunctions, including elevations in hepatic serum biochemistries. Severe hypersensitivity reactions that have been reported are associated with other integrase inhibitors and can occur with Cabotegravir. The use of Cabotegravir should be discontinued if a hypersensitivity reaction is suspected.

• Post-Injection Reactions- During certain clinical trials, cases of serious post-injection reactions were seen within minutes after the injection of Rilpivirine, such as dyspnea (shortness of breath), agitation, flushing, sweating, abdominal cramps, oral numbness, changes in blood pressure. These events were reported in less than one percent of patients. The symptoms began to resolve within a few minutes after the injection. These events may have been associated with partial intravenous administration. The instructions should be followed carefully for use when preparing and administering the medication to avoid accidental intravenous administration. The patients should be observed closely after the injection. If a patient experiences a post-injection reaction, they should be monitored and treated as clinically indicated.

• Hepatotoxicity- Cases of hepatotoxicity have been documented in patients receiving Cabotegravir or Rilpivirine with or without any known pre-existing hepatic disease. Patients with liver disease or a marked increase in transaminases before the treatment can be at risk for worsening transaminase elevations. It is recommended to monitor liver chemistries and if hepatotoxicity is suspected treatment with Cabotegravir should be discontinued.

• Depressive Disorders- Depressive disorders such as depressed mood, depression, altered mood, dysphoria, negative thoughts, and suicidal ideation have been reported with Cabotegravir. The patients should be evaluated with depressive symptoms to determine whether the symptoms are related to Cabotegravir and if the risks of continued therapy outweigh the benefits.

• Risk of Adverse Reactions and Loss of Virologic Response Due to Drug Interactions- The collateral use of Cabotegravir and other drugs may result in drug interactions, and can also lead to adverse events. Hence caution should be taken while using the drug in combination with other drugs with a known risk of Torsade de Pointes (a type of abnormal heart rhythm). Consider the potential for drug interactions before and during therapy with, and after discontinuation of Cabotegravir.

• Long-Acting Properties and Potential Associated Risks with Cabotegravir- Residual concentrations of Cabotegravir and Rilpivirine can remain in the systemic circulation of patients for up to 12 months or longer. It is important to select patients carefully who agree to the required monthly injection dosing schedule as non-adherence to monthly injections or missed doses can further lead to loss of virologic response and develop resistance. To minimize the potential risk of the development of viral resistance, it is necessary to start an alternative, and fully suppressive antiretroviral regimen no later than one month after the final injection doses of Cabotegravir. If virologic failure is suspected, the patient should be switched to an alternative regimen immediately.

For Patients

What Is HIV?

Human immunodeficiency virus (HIV) is a virus that attacks the immune system, specifically the CD4 cells (also known as T cells), which are important for fighting off infections and diseases. HIV gradually weakens the immune system over time, making it harder for the body to fight off infections and illnesses.

If left untreated, HIV can progress to AIDS (acquired immunodeficiency syndrome), which is the most severe stage of the disease. AIDS is characterized by a severely weakened immune system and an increased risk of opportunistic infections, such as pneumonia and tuberculosis, as well as certain types of cancer.

HIV is primarily spread through the exchange of bodily fluids, such as blood, semen, vaginal fluids, and breast milk, during unprotected sexual contact, the sharing of needles or injection equipment, and from mother to child during pregnancy, childbirth, or breastfeeding. There is currently no cure for HIV, but with early diagnosis and proper medical care and treatment, people living with HIV can manage the virus and live long, healthy lives.

How Effective Is Cabotegravir?

In studies of HIV prevention, Cabotegravir has been shown to be highly effective in reducing the risk of HIV transmission. In the HPTN 083 trial, which involved over 4,500 cisgender men and transgender women who have sex with men, Cabotegravir was found to be 66 percent more effective at preventing HIV transmission than the current standard of care.

Things to Inform the Doctor Before Taking Cabotegravir:

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

• In case of hypersensitivity or allergy to Cabotegravir or any of the other ingredients in this medicine or if currently taking medicines such as Carbamazepine, Oxcarbazepine, Phenytoin, Phenobarbital (for epilepsy and preventing fits), Rifampicin or Rifapentine.

• Inform the doctor if there have been or are liver problems, including hepatitis B or C. The doctor may assess the severity of the liver disease before prescribing Cabotegravir. It is not recommended to use Vocabria during pregnancy, but if required, the doctor will weigh the benefits against the risks to the fetus.

• Consult with the doctor in advance if planning to have a baby. Breastfeeding is not recommended for HIV-positive women, as the virus can transmit through breast milk.

What Are the Side Effects of Cabotegravir?

The common side effects of Cabotegravir include

• Headache and reactions at the site of injection (pain, discomfort, a lump, redness, itching, swelling, warmth, bruising, numbness, bleeding, an abscess). Additionally, feeling hot (pyrexia) may occur within one week after injections.

• Mood changes.

• Difficulty sleeping.

• Giddiness.

• Weakness.

Report to the doctor immediately if the following side effects are experienced:

• Allergic Reactions - Symptoms include skin rash, muscle aches, extreme fatigue.

• Infection - Symptoms include muscle weakness or pain, palpitations, joint pain, etc.

What Should Be Done If a Dose Is Missed?

Planned Missed Doses:

If an individual misses a scheduled every-two-month continuation injection visit for more than seven days, the doctor may advise administering daily oral Cabotegravir for up to two months to replace one missed scheduled every-two-month injection. Follow the dosing schedule as instructed by the doctor.

Unplanned Missed Dose:

If a scheduled injection visit is missed or delayed by more than seven days, and oral dosing has not been taken in the interim, the doctor will clinically reassess the individual to determine if resumption of injection dosing remains appropriate. Follow the instructions given by the clinician.

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.

Avoid Self-Medication:

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. The use of Cabotegravir requires careful monitoring by a healthcare provider, including regular blood tests to ensure that the medication is working properly and to check for any potential side effects.

For Doctors

Indication:

• Cabotegravir is used to prevent sexually-acquired HIV-1 infection in at-risk adults and adolescents weighing at least 35 kg.

• Cabotegravir and Rilpivirine combination is used as a complete HIV-1 treatment regimen for adults and adolescents weighing at least 35 kg who are virologically suppressed on a stable antiretroviral regimen, without a history of treatment failure, and no known resistance to Cabotegravir or Rilpivirine.

Dosing:

Pre-exposure Prophylaxis (PrEP) of Sexually Transmitted HIV:

The patient’s tolerability of the medication may be assessed during an optional lead-in phase. The general dosing is as follows:

• With Oral Lead-in: 30 mg oral dose of Cabotegravir daily for at least 28 days, followed by an initial injection of 600 mg of Cabotegravir given in the muscle at months two and three. Followed by an injection of 600 mg is given every two months.

• Without Oral Lead-in: The initial injections are given at months one and two, followed by a 600 mg injection at month four and every two months thereafter.

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 signs or symptoms of acute HIV-1 infection or if HIV-1 antibody test results are positive.

• Adherence: Healthcare providers should choose individuals who are willing to adhere to the necessary injection dosing and testing schedule, and educate them on the significance of following the scheduled dosing appointments to decrease the chances of acquiring HIV-1 infection and the emergence of resistance, before initiating Cabotegravir treatment.

Pharmacology:

Mechanism of Action:

Cabotegravir is an integrase strand transfer inhibitor (INSTI), which works by blocking the action of the integrase enzyme that is essential for the replication of the human immunodeficiency virus (HIV).

Pharmacodynamics:

Cabotegravir blocks the activity of HIV integrase, which lowers the replication of the virus. 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.

Pharmacokinetics:

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 such as albumin and alpha-1 acid glycoprotein. The volume of distribution is approximately 23 liters after intravenous administration. The drug penetrates the blood-brain barrier to some extent.

Metabolism:

Cabotegravir is mainly metabolized by UGT1A1 and CYP3A4 enzymes in the liver. The major metabolic pathway involves glucuronidation of the parent drug to form Cabotegravir glucuronide, which is inactive. A minor pathway involves oxidative metabolism by CYP3A4 to form a pharmacologically active metabolite.

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, both 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 liver problems worsening. Monitoring is recommended for these patients and treatment should be discontinued if there are indications of liver damage.

• Psychiatric: The drug has been associated with depressive disorders such as changes in mood. It is important to evaluate patients who show such symptoms and consider the benefits and risks of continuing the therapy.

• Others: To avoid adverse effects such as loss of virologic response and possible development of viral resistance, it is important to review any medications that are 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 - Residual concentrations of Cabotegravir and Rilpivirine may remain in the systemic circulation of patients for up to 12 months or longer. 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 with some contribution from the UGT1A9 gene. Drugs that are strong inducers of the UGT1A1 gene or 1A9 tend to decrease Cabotegravir plasma concentrations and can also result in loss of virologic response, hence, coadministration of Cabotegravir with these drugs is contraindicated.

Other Specifications:

• Pregnancy- Insufficient human data is available on the use of Cabotegravir during pregnancy to properly assess a drug-associated risk of birth defects and miscarriage. Cabotegravir and Rilpivirine can be found in the systemic circulation for up to twelve months or longer even after the discontinuation of Cabotegravir injections, hence, the potential for fetal exposure during pregnancy should be considered.

• Lactation- The Centers for Disease Control and Prevention (CDC) recommends that HIV-1−infected mothers should not breastfeed their infants to avoid the risk of postnatal transmission of HIV-1 infection. It is unknown if the components of Cabotegravir are present in human breast milk, affect human milk production, or have effects on the breastfed infant. 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 numbers of 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 other drug therapy.

• Renal Impairment- According to studies with oral Cabotegravir and oral Rilpivirine, no dose adjustment of Cabotegravir is required for patients with mild or moderate renal impairment. For patients suffering from severe renal impairment or end-stage renal disease, monitoring should be increased for adverse effects.

• Hepatic Impairment- According to separate studies with oral Cabotegravir and oral Rilpivirine, no dose adjustment of Cabotegravir is required for patients with mild or moderate hepatic impairment. In the case of severe hepatic impairment, the effect on the pharmacokinetics of Cabotegravir or Rilpivirine is not known.