Pomalidomide

Pomalidomide is an antineoplastic agent belonging to the pharmacological class of immunomodulatory agents.

The FDA approved Pomalidomide for treating Multiple Myeloma (MM) and AIDS-related Kaposi sarcoma (KS).

Pomalidomide enters the bloodstream quickly—between two and three hours—and is less readily absorbed from high-fat foods. It shows an apparent volume of distribution (62-138 L), considerable diffusion into semen (about 67%), and plasma protein binding (12-44%). It is metabolised mainly by the liver, which uses CYP1A2 and CYP3A4. Urine contains 73% of the drug's excretion.

The most common side effects of Pomalidomide include fatigue, fever, bone pain, muscle cramps, and diarrhea.

Pomalidomide is available in oral capsules.

The molecule is available in India, the United States, Switzerland, Canada, countries within the European Union, Australia, Argentina, Japan and South Korea.

Pomalidomide is an antineoplastic agent belonging to the pharmacological class of immunomodulatory agents.

Pomalidomide is shown to stop tumour cells from proliferating and to cause them to undergo apoptosis. Pomalidomide also improves immunity mediated by T cells and natural killer (NK) cells, preventing monocytes from producing pro-inflammatory cytokines such as IL-6 or TNF-alpha. It is believed that Pomalidomide primarily targets the protein cereblon. It attaches itself to this target and prevents ubiquitin ligase function. Moreover, it inhibits COX2 transcription.

Pomalidomide reaches peak plasma time approximately 2-3 hours after dosing in patients with multiple myeloma (MM) or Kaposi's sarcoma (KS).

The peak plasma concentration of Pomalidomide is 75 ng/mL in multiple myeloma (MM) patients and 53.1 ng/mL in Kaposi's sarcoma (KS) patients.

Pomalidomide is available in oral capsules.

Capsules: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once daily, with or without food.

Pomalidomide is indicated in the following health conditions:

• In patients with multiple myeloma (MM) who had at least two previous treatments, such as lenalidomide and a proteasome inhibitor, and who have disease progression on or within 60 days following the last therapy's completion. When used with dexamethasone.
• For individuals with AIDS-related kidney failure who did not respond to highly active antiretroviral treatment (HAART).
• For individuals who are HIV-negative for KS.

Orally: Pomalidomide is available in capsules and is administered orally. It is advisable to take it without food, at least 2 hours before or after a meal. The capsules should be swallowed whole, not crushed, chewed, or opened. In the case of a missed dose, patients should skip the missed dose and resume the standard dosing schedule. Caution is advised for pregnant or breastfeeding individuals.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Pomalidomide is available in oral capsules.

Dose Adjustment in Adult Patients:

• Multiple Myeloma

Administer low-dose dexamethasone in combination with 4 mg PO qDay on Days 1 to 21 of repeated 28-day cycles until disease progression.

Low-level dexamethasone administration

Low-dose dexamethasone

Only administer PO on Days 1, 8, 15, and 22 of every 28-day cycle

≤75 years: 40 mg per day

>75 years: 20 mg per day

• Kaposi Sarcoma

AIDS-related Kaposi sarcoma (KS)

5 mg PO qDay on Days 1-21 of each 28-day cycle

Continue until disease progression or unacceptable toxicity

Continue HAART as part of HIV treatment

In adults with KS who are HIV-negative

On Days 1–21 of every 28-day cycle, 5 mg PO qDay

Continue until the disease worsens or the toxicity becomes unacceptable.

Patients can actively manage side effects by altering their diet while receiving Pomalidomide treatment. Consume nutrient-rich foods, such as leafy vegetables, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, cauliflower, cabbage, broccoli, beans, and herbs to promote overall health. Steer clear of harmful habits by avoiding smoking and alcohol consumption. Choose a healthier lifestyle by eliminating fast food, fried items, processed meats, refined carbohydrates, and added sugars from your diet.

The dietary restriction should be individualized as per patient requirements.

• In individuals who have a history of excipient or active drug hypersensitivity (e.g., angioedema, anaphylaxis).
• Pregnancy

• Increased Mortality: Pembrolizumab has been linked to a higher death rate in people with multiple myeloma when combined with dexamethasone and an analogue of thalidomide.
• Hematologic Toxicity: Neutropenia, the most commonly reported Grade 3/4 adverse event, must be closely watched, mainly when neutropenia is present.
• Hepatotoxicity: Because of the potential risk of hepatotoxicity, which includes hepatic failure and mortality, monthly monitoring of liver function tests is crucial.
• Excessive sensitivity responses: Immediately report occurrences of angioedema and severe dermatologic reactions so that Pomalidomide can be stopped.
• Tumor Lysis Syndrome (TLS): Consider steps to prevent it, be cautious, and monitor for any signs and symptoms in patients who are at risk of TLS, especially those who have a high number of tumours.

The adverse reactions related to Pomalidomide can be categorized as:

• Common Adverse Effects: Fatigue, constipation, diarrhoea, anaemia, neutropenia, thrombocytopenia, and peripheral oedema.
• Less Common Adverse Effects: Infections, febrile neutropenia, pneumonia, urinary tract infections, and gastrointestinal perforations.
• Rare Adverse Effects: Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema. Hematologic toxicities, such as deep vein thrombosis and pulmonary embolism, have been reported.

Reports from postmarketing

Disorders of the blood and lymphatic system: pancytopenia

Diabetes mellitus: hypothyroidism and hyperthyroidism

gastrointestinal issues: bleeding in the gastrointestinal tract

Hepatobiliary disorders: increased liver enzymes, hepatic failure

Immune system problems include solid organ transplant rejection and allergic responses (such as urticaria, angioedema, and anaphylaxis).

Reactivation of the hepatitis B virus, herpes zoster, and progressive multifocal leukoencephalopathy (PML) are examples of infections and infestations.

Skin neoplasms that are benign, malignant, or unclear include skin squamous cell carcinoma, basal cell carcinoma, and tumour lysis syndrome.

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, eosinophilia-associated drug reaction, and systemic symptoms (DRESS)

The clinically relevant drug interactions of Pomalidomide are briefly summarized here.

• Drug Interactions: Pomalidomide may interact with antipsychotic drugs (such as clozapine), immunomodulatory drugs (such as baricitinib, fingolimod, and leflunomide), and cancer treatments (such as adalimumab and avelumab).
• Food Interactions: Avoid the consumption of alcohol.
• Disease Interactions: Allow the physician to know if one has low blood counts or depression in your bone marrow, arterial thromboembolic events (stroke and myocardial infarction), thromboembolic events (deep vein thrombosis and pulmonary embolism), renal or hepatic impairment, or infections (Bacterial, Fungal, Protozoal, or Viral).

The common side effects of Pomalidomide include:

Fatigue

Nausea

Diarrhea

Constipation

Anemia

Neutropenia (low levels of neutrophils)

Thrombocytopenia (low levels of platelets)

Upper respiratory tract infections

Back pain

Peripheral oedema (swelling, typically in the legs and ankles)

• Pregnancy

Pregnancy Category(FDA) X: When pregnant, avoid using. The risks outweigh the potential benefits. There are safer alternatives available.

Not recommended during pregnancy

When given to a pregnant woman, embryofetal damage may be based on the mechanism of action and results from animal studies.

If pregnancy does develop while on treatment, stop the medication right once and send the patient to a gynaecologist or obstetrician with experience in reproductive toxicity for additional assessment and guidance.

Assess the status of potential mothers' pregnancies before starting treatment and during it.

Animal data

When given during organogenesis, teratogenic effects are shown in both rats and rabbits.

administered to pregnant rabbits and allowed to cross the placenta.

Inform the patient about the possible danger to the baby if this medication is used during pregnancy or if the patient gets pregnant while taking it.

Registry of pregnancy exposure

The registry examines the results of pregnancies for women who are exposed to drugs while they are pregnant, as well as for the female partners of men who are exposed to drugs.

Contraception

Males who can reproduce with a female partner.

Men who use drugs have drug residue in their semen.

Must always wear a latex or synthetic condom when having intercourse with women who are fertile while taking medication and for up to four weeks after stopping treatment, even if the woman has had an effective vasectomy.

Male patients who use drugs are not permitted to give sperm.

Lack of conception

Treatment may impair female fertility, according to research on animals.

Women who are capable of having children

Must commit to either abstain from heterosexual sexual activity entirely or to use two highly effective birth control methods concurrently: one highly effective method (such as tubal ligation, IUD, hormonal birth control, injections, patches, vaginal rings, or implants), partner vasectomy, or another highly effective method (such as male latex or synthetic condom, diaphragm, or cervical cap).

Contraception has to start four weeks before treatment starts, continue for four weeks throughout therapy, stop for dose adjustments, and continue for four weeks after treatment ends.

Contraception is recommended even in cases when infertility has already occurred unless a hysterectomy was the cause; see an authorized provider of contraceptive techniques if necessary.

• Nursing Mothers

There is no information available regarding Pomalidomide's presence in human milk, its effects on a breastfed kid, or its impact on milk production. The milk produced by nursing rats contained Pomalidomide. Advise women not to breastfeed while on Pomalidomide therapy since many medications are excreted in human milk and because there is a chance that the medicine will have adverse side effects in a developed breast.

Animal Data

When nursing rats were given Pomalidomide orally once, around 14 days after giving birth, the drug was incorporated into their milk at a ratio of 0.63 to 1.46 compared to plasma.

• Pediatric Use

As per FDA, the safety and effectiveness have not been established in pediatric patients.

Dose Adjustment in Kidney Impairment Patients:

Severe

Reduce to 3 mg/day if sufficiently severe to require hemodialysis (MM).

Reduce to 4 mg/day if sufficiently severe to require hemodialysis (KS).

After the procedure is finished, undergo hemodialysis for a few days.

Dose Adjustment in Hepatic Impairment Patients:

MM: Moderate to mild (Child-Pugh A or B): Reduce down to 3 mg daily

Reduce to 2 mg/day for severe cases (Child-Pugh C).

KS: Reduce to 3 mg/day for mild-to-severe (Child-Pugh A to C) cases.

There have been no known cases of Pomalidomide overdose. There is no antidote for Pomalidomide. However, hemodialysis can remove pomalidomide from circulation.

• Absorption: The gastrointestinal system absorbs Pomalidomide very quickly. The presence of food reduces absorption rate and extent, especially in high-fat and high-calorie meals.
• Distribution: This medication is widely distributed, entering semen at a rate of about 67%. The apparent volume of distribution shows a broad dispersion throughout body tissues, ranging from 62 to 138 L. The binding of plasma proteins ranges from 12% to 44%.
• Metabolism: The liver is the main site of metabolism, where the processes of glucuronidation or hydrolysis follow hydroxylation. Hepatic enzymes are principally responsible for this metabolic change, with CYP1A2 and CYP3A4 having significant functions. The roles of CYP2C19 and CYP2D6 are minimal.
• Excretion: Pomalidomide is mostly removed via urine, approximately 73%, with 2% left unchanged. Feces comprise about 15% of the secondary route of elimination, with 8% of the drug left unchanged. Pomalidomide's elimination half-life in multiple myeloma patients is around 7.5 hours. This half-life is approximately 9.5 hours in healthy individuals.

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• https://www.ncbi.nlm.nih.gov/books/NBK548343/
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204026s019lbl.pdf
• https://www.ema.europa.eu/en/documents/product-information/imnovid-epar-product-information_en.pdf