Maribavir for Post-transplant CMV Infection

For Patients

What Is Maribavir?

Maribavir is a prescription medicine that fights viruses. It is mainly used to treat cytomegalovirus (CMV) infections in patients who have had organ transplants and whose infections are resistant to other medicines like Ganciclovir, Cidofovir, Valganciclovir, and Foscarnet. It belongs to a group of drugs called Benzimidazole ribosides. Maribavir can be given to adults and children aged 12 years and older.

What Is Post-transplant CMV Infection?

Cytomegalovirus (CMV) is a type of herpes virus (the same family of viruses that causes cold sores). In healthy people, CMV usually does not cause any problems, but in patients with weak immune systems, such as after organ transplants or in HIV/AIDS, it can become dangerous.

CMV spreads through body fluids like saliva, blood, breast milk, or during organ transplantation and close contact with infected people. It can infect someone for the first time (primary infection), return after being inactive (reactivation), or infect someone who was already infected before (reinfection).

In transplant patients, reactivation of CMV is common. It can increase the risk of the body rejecting the new organ and can cause problems like:

• Graft dysfunction (organ not working properly).

• Coronary artery atherosclerosis (narrowing of heart arteries).

• Drug-resistant CMV infection.

• A weak immune system causes other infections.

Symptoms usually appear one to four months after a transplant and can include:

• Fever.

• Chills.

• Diarrhea.

• Fatigue (extreme tiredness).

• Muscle aches.

• Swollen lymph nodes.

CMV infections after transplant are usually treated with oral or intravenous antiviral medications. With modern medicine, the prevention of CMV infections has improved a lot over the past few years.

How Does Maribavir Work?

Maribavir is an antiviral medicine. It works by stopping an enzyme called pUL97 in the CMV virus, which the virus needs to multiply. By doing this, Maribavir blocks the virus from making its proteins, copying its DNA, packaging itself, and leaving the cell to infect other cells.

Studies show that Maribavir works better than some other antiviral medicines for treating CMV in patients who have had organ or stem cell transplants. However, it is not very effective if given just to prevent CMV after a transplant.

Indications of Maribavir

• Adults and children over 12 years with post-transplant CMV infections that are resistant to Ganciclovir, Cidofovir, Foscarnet, or Valganciclovir.

• It may also be used for multidrug-resistant CMV infection in patients with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).

Contraindications of Maribavir

Maribavir is not recommended for pregnant or lactating women, children below 12 years, or patients with severe hepatic disorders. Maribavir comes as 200 mg tablets. The usual dose for adults and children over 12 is 400 mg (two tablets) twice a day, with or without food.

If taken with certain medicines, the dose may need to be increased:

• With Carbamazepine: 800 mg (four tablets) twice daily.

• With Phenytoin or Phenobarbital: 1200 mg (six tablets) twice daily.

• Immediate-release tablets can be taken whole, crushed, or dissolved in water. If the patient cannot swallow, the medicine can be given through a tube into the stomach. The dissolved solution can be kept at room temperature for up to eight hours.

Warnings and Precautions

• Maribavir can stop working in some cases if the virus becomes resistant, which can happen during or after treatment, even four to eight weeks after stopping. Therefore, doctors need to monitor CMV DNA levels and check for resistance if the infection does not improve or returns.

• Maribavir may interact with some other medicines, making them less effective or causing side effects. It should never be given with Ganciclovir or Valganciclovir, because it blocks their action.

• It can also increase the level of immunosuppressants (medicines that lower the immune system), so regular monitoring and dose adjustments are necessary.

Adverse Effects of Maribavir

Adverse effects of Maribavir include:

• Nausea and vomiting.

• Diarrhea.

• Fatigue (excessive tiredness).

• Taste disturbances.

• Skin rash.

• Itching.

• Swelling of the face, tongue, and throat.

• Difficulty breathing.

• Severe dizziness.

• Mouth sores.

• Pale skin.

• Fever and chills.

How Effective Is Maribavir?

Maribavir is very effective for treating CMV infections in high-risk patients, such as those with HIV/AIDS or who have had transplants. Clinical studies show it works better than Ganciclovir, Valganciclovir, Cidofovir, and Foscarnet in these patients. It is generally safe but can cause side effects and should not be used with Ganciclovir or Valganciclovir.

How Should Maribavir Be Taken?

Maribavir must be taken exactly as prescribed. Usually, it is taken twice a day with or without food. The tablets should be swallowed whole, but if necessary, they can be crushed and mixed with water for tube administration.

What Are the Side Effects of Maribavir?

The side effects of Maribavir include:

• Nausea and vomiting.

• Taste changes.

• Diarrhea.

• Fatigue.

• Fever.

• Chills.

• Difficulty breathing.

• Mouth sores.

• Dizziness.

• Pale skin.

• Swelling of the face, tongue, and throat.

• Skin rash, itching.

What Must the Patient Inform the Doctor Before Taking Maribavir?

• Before taking Maribavir, female patients must inform their doctor if they are pregnant, planning pregnancy, or breastfeeding, as it may harm the baby.

• Before starting treatment with Maribavir, patients must inform the doctor if they take any vitamins, herbal or nutritional supplements, over-the-counter drugs, or other medications.

• Patients must inform the doctor if they take seizure (uncontrolled body movements) medicines or other anticonvulsants before taking Maribavir. Any new medication must not be started without consulting the doctor.

• Patients must inform the doctor if they are allergic to any medications before starting the treatment.

What Are the Precautionary Measures to Be Followed While Taking Maribavir?

• Regular checkups may be recommended by the doctor during the treatment with Maribavir to ensure that the drug is working effectively.

• Maribavir must not be used with Ganciclovir or Valganciclovir.

• Maribavir can interact with certain drugs, affect the way other medicines work, or cause adverse effects. In such situations, the prescribing doctor must be consulted immediately.

• Patients or caregivers must inform the doctor immediately in case of side effects or serious adverse reactions.

Missed dose

If a dose is missed, take it as soon as remembered. If it is almost time for the next dose, skip the missed one. Do not take two doses at the same time.

Overdose

In case of overdose or serious side effects, contact your doctor immediately for proper treatment.

Storage

Maribavir tablets must be stored in their original containers at temperatures between 20 and 25 degrees Celsius (68 and 77 degrees Fahrenheit), away from excess heat and moisture, and out of reach of children.

For Doctors

Pharmacological Aspects of Maribavir

Mechanism of action

Maribavir exhibits antiviral activity mediated by the competitive inhibition of the human CMV pUL97 viral protein kinase enzyme. It also prevents protein phosphorylation and other processes such as CMV DNA replication, encapsidation, and nuclear egress.

The mechanism of action of Maribavir is different from that of other antiviral agents that inhibit DNA polymerase enzymes. Maribavir is highly effective against CMV strains resistant to drugs such as Ganciclovir, Cidofovir, Foscarnet, and Valganciclovir.

Pharmacodynamics

Studies have shown that Maribavir exerts antiviral efficacy through an alternative target mechanism compared to traditional CMV antiviral agents. Hence, it is useful in treating CMV infections that are refractory to standard therapy.

Maribavir must not be used with Ganciclovir or Valganciclovir, as they need activation via CMV pUL 97 to exert antiviral activity. Therefore, taking Maribavir with these drugs can significantly reduce the antiviral activity.

Pharmacokinetics

• Absorption: After an oral administration of a single dose of 50 to 1600 mg of Maribavir and multiple doses of up to 2400 mg/day (milligram/day), the plasma concentration increased dose-proportionally, and the area under the curve ranged from 1.37 to 1.47. The time taken to achieve maximum plasma concentration (Tmax) was about one to three hours.

• Distribution: Maribavir gets extensively bound to plasma proteins (98 percent) across all the tested concentrations, and the mean apparent volume of distribution was 24.9 L (liters).

• Metabolism: After an oral administration, Maribavir is extensively metabolized into its major metabolite VP 44469 by CYP2A4 and CYP1A2 enzymes.

• Excretion: Maribavir gets eliminated mainly via hepatic metabolism, and the mean half-life is approximately 4.32 hours. The mean oral clearance in post-transplant patients was around 2.85 L/h (liters per hour). After an oral administration of radiolabeled Maribavir, approximately 61 percent and 14 percent of the dose were excreted in urine and feces, respectively.

Drug Interactions

Some of the drugs that interact with Maribavir include:

• Allopurinol.

• Afatinib.

• Avanafil.

• Carbamazepine.

• Phenobarbital.

• Methadone.

• Ganciclovir.

• Repotrectinib.

• Tramadol.

• Rifampin.

• Apalutamide.

• Budesonide.

• Enzalutamide.

• Phenytoin.

Clinical Studies

A phase 3, multicenter, open-label, randomized, active-controlled superiority trial was conducted to evaluate the safety and efficacy of Maribavir compared to investigator-assigned treatment (IAT) with Ganciclovir, Valganciclovir, Cidofovir, or Foscarnet for CMV infections that were resistant to these drugs. The mean age of the subjects was 53 years; they were randomized in a ratio of 2:1 to receive either Maribavir (400 mg twice daily) or any of the IAT for up to eight weeks.

The most common drug administered was Foscarnet (41 percent), followed by Ganciclovir and Valganciclovir (24 percent each), Cidofovir (six subjects), a combination of Valganciclovir and Foscarnet (four patients), and a combination of Ganciclovir and Foscarnet (three subjects).

After the completion of treatment, the subjects were involved in a 12-week follow-up phase. The primary endpoint was noted as Maribavir being statistically superior to IAT, and the treatment effect was consistent across age groups, transplant type, and the presence of CMV disease or syndrome. However, Maribavir was less effective in subjects with increased CMV DNA levels and no genotypic resistance.

Nonclinical toxicology

• Carcinogenicity: Two-year carcinogenicity studies have shown that Maribavir was not carcinogenic at doses up to 150 and 100 mg/kg/day (milligram per kilogram per day) in mice and rats, respectively.

• Mutagenicity: Maribavir was negative in the bacterial mutation and in vivo micronucleus assays.

• Impairment of fertility: Animal studies have shown that Maribavir did not cause any significant effects on fertility in male and female rats.

Specific considerations

• Pregnancy: Adequate information is not available to establish whether Maribavir can pose a risk to pregnant women or the fetus. Therefore, it must be avoided in pregnancy.

• Lactation: It is not determined whether Maribavir or its metabolites are present in human milk or whether they affect breastfed infants or milk production.

• Pediatric use: The safety and effectiveness of Maribavir have not been determined in children below 12 years of age.

• Geriatric use: Dose modification of Maribavir is not recommended for patients over the age of 65 years, as no significant changes were observed compared to younger adults.

• Hepatic and renal impairment: Maribavitr is not recommended in patients with severe hepatic impairment. Dose modification of Maribavir is not necessary for patients with mild or moderate hepatic disorders or mild, moderate, or severe renal disorders.