Alpelisib - Indications, Pharmacology, Warnings and Precautions

Overview:

Alpelisib is a cancer-fighting drug that inhibits the phosphatidylinositol 3-kinase (PI3K) enzyme, especially its p110α subunit. Several malignancies frequently harbor mutations in this enzyme, leading to aberrant cell proliferation. Alpelisib's purpose is to target and block this mutant enzyme specifically.

For the therapy of advanced or metastatic breast cancer in postmenopausal women and men, Alpelisib medication is used along with another cancer medicine, Fulvestrant. It is essential to use Food and Drug Administration (FDA)-approved diagnostic tests to confirm the existence of a specific mutation (PIK3CA) before beginning Alpelisib medication. This medicine is only helpful for breast cancers with a PI3K mutation.

The FDA approved Alpelisib on May 24, 2019, for advanced breast cancer, which is positive for hormone receptor and negative for human epidermal growth factor receptor 2, along with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutation. However, Alpelisib’s FDA approval for treating adults and children with PIK3CA-Related Overgrowth Spectrum (PROS) who need systemic therapy was granted in April 2022.

Drug Group:

Alpelisib belongs to a group of drugs known as kinase inhibitors. It functions as a cancer treatment by halting the signals that encourage malignant tumor cells to continue growing, stopping cancer cell spread. The drugs in this group can block the impulses that cause overgrowth and abnormalities in particular body tissues. This helps reduce the size of the overgrowth and, in turn, relieves the symptoms in PROS patients.

For Patients:

What Is Alpelisib?

Alpelisib is a highly potent cancer medicine that works against certain types of breast cancer. It is mostly used in combination with other cancer medicines rather than as a single-agent therapy. It is available in tablet form, making it a convenient choice for cancer patients. However, Alpelisib’s side effects must also be considered during therapy, as it is not free of them. Current research is examining the efficacy of Aleplisib in treating malignancies other than breast cancer, such as colorectal and ovarian cancer.

Why Is Alpelisib Medication Prescribed?

Alpelisib is used in combination with another cancer medicine called Fulvestrant to treat a specific kind of breast cancer. It is used for men whose cancer worsened during or after certain other treatments, or for women who have already undergone menopause (the end of their menstrual periods) and whose cancer has migrated to adjacent tissues or different regions of the patient's body.

Adults and children (two years of age and older) with certain forms of PIK3CA-related overgrowth spectrum (a hereditary disorder that causes overgrowth and abnormalities in specific tissues) are also treated with Alpelisib.

As Alpelisib breast cancer treatment specifically targets the PIK3CA mutation, it can offer better therapeutic outcomes when advocated for in indicated cases.

How Should Alpelisib Be Used?

• Alpelisib is available as an oral tablet. Usually, it is taken once a day with food as per the physician's prescribed treatment plan. Take Alpelisib daily at approximately the same time.

• Administer Alpelisib as prescribed. Never take more or less of it or more frequently than the doctor has instructed.

• Do not split, chew, or crush the tablets; swallow them whole. Take care not to take any damaged, cracked, or broken tablets.

• You can dissolve the pills in water, especially when it is advised for a child with PROS, who finds it difficult to take the whole tablet. Put the tablet(s) into a glass of water containing 2 to 4 ounces (60 to 120 milliliters). After 5 minutes, smash the tablets and stir the mixture with a spoon. Consume the blend right away. Add 2 to 3 tablespoons of water to the glass using the same spoon, then whisk to rinse.

• Do not take another dose of Alpelisib if you throw up after taking it. Maintain the usual dosage regimen. If you encounter certain side effects, the doctor may reduce the amount of Alpelisib you take. Doctors might also treat you with different drugs or halt or modify the treatment.

• Ensure you let the doctor know how you feel while taking Alpelisib.

What Alpelisib Precautions Should I Follow?

• If you have an allergy to any of the substances in Alpelisib tablets, other drugs, herbal products, or Alpelisib itself, let the doctor and chemist know.

• Inform the physician and chemist of all your prescribed medications, minerals, and supplements with nutrients that you now take or intend to take. Alpelisib may interact with an over-the-counter medication called St. John's Wort. Before you begin taking Alpelisib, make sure your doctor and pharmacist are aware of all the medications you are taking.

• The doctor might need to carefully monitor you, check for any adverse effects, and tweak drug dosages to align.

• Inform the physician if you currently have diabetes or kidney illness, or if you have ever experienced a rash with red sores on the lips, mouth, or skin, or flaking, blistering skin, or have previously suffered from diabetes or kidney illness.

• While taking Alpelisib, avoid starting any new medications without first talking to your doctor.

• Patients on Alpelisib should let their doctors know if they intend to get pregnant or if they are already pregnant with their partners. It is important to remember that while taking Alpelisib, neither the patient nor their partner should try to get pregnant.

• You must take a pregnancy test before starting therapy if you are a female.

• You should also use reliable birth control during the treatment and for one week following the last dosage. Inform the doctor if the partner becomes pregnant while taking Aleplisib.

• According to experts, breastfeeding should be avoided during therapy or for one week following the last dose.

• You need to be aware that this medicine may lower both men's and women's fertility. Keep yourself aware of the potential hazards of using Aleplisib.

What Are the Side Effects of Alpelisib?

Side effects are possible with Alpelisib. If one experiences any of the following side effects while taking Alpelisib, contact the doctor immediately:

• Weakness or fatigue.

• Blurred vision.

• Excessive thirst.

• Frequent urination.

• Severe hunger.

• Nausea and vomiting.

• Diminished hunger.

• Alteration in the flavor of the food.

• Weight reduction.

• Stomach ache.

• Reflux.

• Hair thinning.

• Migraine.

• Itching.

• Dry skin.

• Mouth dryness.

• Oral sores.

• Dryness in the vagina.

• Fever.

• Edema in arms and legs.

An individual should be aware that Alpelisib may elevate blood sugar levels. Check your blood sugar as often as your physician prescribes, especially if you have diabetes or high blood sugar.

Call the doctor if the blood sugar is higher than normal. Since untreated high blood sugar can lead to a dangerous state known as ketoacidosis, it is advised to contact the doctor urgently in case symptoms appear. If ketoacidosis is not treated on time, it could turn fatal. Ketoacidosis is characterized by altered consciousness, fruity breath, upset stomach and vomiting, and dry mouth.

When using Alpelisib for breast cancer, if one gets nausea, vomiting, or diarrhea that prevents one from eating or drinking regularly, contact the doctor right away. While using Alpelisib, the doctor might need to adjust the diet or medications to help control blood sugar.

Certain adverse effects may be dangerous. Call the doctor right away or seek emergency medical attention if you develop any of the following symptoms:

• Breathing or swallowing difficulties, rash, hives, flushing, fever, or rapid pulse.

• Swelling in the hands, feet, ankles, eyes, throat, tongue, lips, and lower limbs.

• Rash; lips, eyes, or mouth blistering; blistering, peeling, or reddish skin.

• Fever.

• Flu-like symptoms.

• Breathing difficulties and shortness of breath.

• Chest pain.

• Coughing.

• Severe diarrhea, parched lips,

• Cramps.

• Weakness.

• Decreased urine production.

• Ankle or leg swelling.

• Diarrhea that is red or watery, and a stomachache.

• Urinating frequently, painfully, or urgently.

Other side effects are also possible with Alpelisib. Contact the doctor immediately if you notice any unusual side effects while taking this medicine.

How Should One Proceed if One Overdoses?

Individuals should take the missed dose as soon as they recall. However, if more than 9 hours have passed since the missed dose, they should omit it and stick to the usual dosing plan. Never take two doses to make up for a missed dose.

What Is the Proper Way to Store and Discard This Medication?

Store this medication tightly closed, out of the children’s reach, and in the original container. Keep it out of the bathroom, away from excessive heat, and at room temperature. Many prescription enclosures (such as every-week pill minders in comparison to those for drops for sight, creams, revisions, and ventilators) are not child-resistant, and tiny minors can quickly open them. It is crucial to keep all medication out of sight and reach of children. Always secure the safety caps on medications to prevent accidental ingestion by small children.

For Doctors:

Indications:

For the treatment of postmenopausal women and men with advanced or metastatic breast cancer, Aleplisib, in conjunction with Fulvestrant, is recommended. Hormone receptor (HR) positivity, human epidermal growth factor receptor 2 (HER2) negativity, and PIK3CA mutation are required to consider this cancer medication as an effective choice. After the cancer progresses on or after an endocrine-based therapy, all these parameters must be assessed and found using a test approved by the FDA.

In addition, systemic medication is utilized to treat adults and children two years of age and older who have severe signs of PIK3CA-related overgrowth spectrum (PROS). This indication is approved under the rapid approval process.

Contraindications:

Alpelisib is contraindicated in patients with a history of allergic or hypersensitivity reactions to Alpelisib. It is also not advised for those with a history of skin diseases like toxic epidermal necrolysis, Stevens-Johnson syndrome, or erythema multiforme.

Moreover, the other contraindications for Alpelisib are as follows:

• Uncontrolled diabetes.

• Pregnancy.

• Breastfeeding.

• People with fertility issues.

• People who are allergic to Alpelisib.

What Are the Pharmacological Aspects of Alpelisib?

1. Mechanism of Action:

Phospholipidinositol-3-kinase is the enzyme that is inhibited by Alpelisib. It primarily inhibits PI3Kα, which is the catalytic α-subunit of PI3K. Gain-of-function mutations in the PIK3CA gene, which codes for the catalytic α-subunit of PI3K, result in cellular transformation, tumor development in both in vitro and in vivo models, and activation of PI3Kα and Akt-signaling.

Alpelisib demonstrated efficacy in cell lines harboring PIK3CA mutations and suppressed the phosphorylation of PI3K downstream targets, including Akt, in breast cancer cell lines. This explains Alpelisib’s mechanism of action in breast cancer cases.

In xenograft models, including breast cancer models, Alpelisib suppressed PI3K/Akt signaling and reduced tumor growth in vivo. It has been demonstrated that treating breast cancer cells with Alpelisib, a PI3K inhibitor, increases ER (endoplasmic reticulum) transcription. In xenograft models derived from ER-positive, PIK3CA-mutated breast cancer cell lines, Alpelisib plus Fulvestrant demonstrated greater antitumor activity than either treatment alone.

2. Pharmacodynamics:

Alpelisib does not prolong the QTcF interval. Patients on Alpelisib benefit from treatment in proportion to the dose, with a 200 mg (milligrams) daily dose showing a 51 percent advantage over a 100 mg (milligrams) dose, and a 300 mg once-daily dose showing a 22 percent advantage over a 150 mg twice-daily dose. This implies that twice-daily dosing may benefit people who require a lower dose.

3. Pharmacokinetics:

• Absorption: After two hours, Alpelisib's plasma concentration peaks at 1320±912ng/mL (nanogram per milliliter). The AUClast and AUCINF of Alpelisib are 11,100±3760h and 11,100±3770h ng/mL, respectively. A little lunch with low-fat content raises the AUC by 77 percent and Cmax by 145 percent, whereas a substantial meal with high-fat content increases the AUC by 73 percent and Cmax by 84 percent.

• Volume of Distribution: At a steady state, the apparent volume of distribution is 114L.

• Binding of Proteins: 89 percent of Alpelisib is bound to proteins.

• Metabolism: The major metabolite of Alpelisib is produced through hydrolysis processes. CYP3A4.7 also metabolizes it. Although the entire metabolism of Alpelisib is unknown, several reactions have been suggested. The primary metabolic process results in the formation of the metabolite M44,5 or BZG791. Alpelisib can also be converted into the M1 and M12 metabolites via glucuronidation.

• Route of Elimination: Oral dosage is excreted in the feces in two forms: 36% as the unaltered medication and 32% as the main metabolite, BZG791. Roughly 2 percent of an oral dosage is excreted in the urine as the medication is unaltered, and 7.1 percent is excreted as the main metabolite BZG791. An oral dose is excreted in the feces 81 percent of the time and in the urine 14 percent.

• Half-Life: Alpelisib has an average half-life of eight to nine hours.

• Clearance: 39.0 L/h (liters per hour) was the average apparent oral clearance. 4 9.2 L/hr is the estimated clearance in fed conditions.

Warnings:

• If the person experiences a severe hypersensitivity reaction, they should immediately discontinue the medication.

• If the person experiences severe skin reactions, they should permanently discontinue the medication.

• In some cases, people may experience severe hyperglycemia. Before taking Alpelisib, tests should be performed to assess blood sugar levels, including fasting plasma glucose, and to optimize blood glucose control. Before initiating treatment with Alpelisib, the person should take Metformin, as it reduces the severity and incidence of hyperglycemia.

• Alpelisib may cause diarrhea, which can result in severe dehydration and acute kidney injury. The healthcare provider may advise the person to take antidiarrheal drugs and increase fluid intake. Additionally, the person should check for blood or mucus in the stool.

• Alpelisib may cause fetal harm. So, this medication is contraindicated for pregnant women.

Overdose:

Overdosed individuals may exhibit rash, nausea, asthenia, and hyperglycemia. Alpelisib overdoses have no known antidote; hence, the patients get only symptomatic treatment. Information on an LD50 (lethal dose 50) is not easily accessible. Patients received doses of up to 450 mg once daily during clinical trials.

Use in Specific Populations:

• During Pregnancy: Alpelisib is not indicated for pregnant women. It carries the risk of fetal harm if taken during pregnancy. That is why a pregnancy test is run before starting Alpelisib.

• During Breastfeeding: Lactating women, if advised to take Alpelisib, then breastfeeding should stop breastfeeding while on treatment. Also, breastfeeding can resume one week after the final dose of Alpelisib.

• Pediatric Population: Alpelisib is not recommended for pediatric use. Its safety and efficacy profiles have not been studied for infants and children.

• Geriatric Population: Alpelisib use in geriatrics showed similar effectiveness to that in adults. But it is often associated with grade three or four hyperglycemia.