Table of Contents
Overview
Sonidegib is a medication used for the treatment of basal cell carcinoma (BCC), a type of skin cancer in adults. It is an antineoplastic agent in the class of drugs called hedgehog pathway inhibitors. BCC is a type of skin cancer that is caused mainly by sun exposure. The drug is indicated to treat BCC in cases where the condition has recurred after surgery or radiation or if it is not treatable with surgery or radiation. The United States Food and Drug Administration (US FDA) approved the drug in July 2015 for basal cell carcinoma. Therefore, the articles unveil the uses, side effects, contraindications, clinical pharmacology, drug interactions, and warnings and precautions for Sonidegib.
Indications
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Basal cell carcinoma (skin cancer type).
Dose Form and Strength
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The drug is available in capsule form and is in strength at 200 mg (milligrams).
For Patients:
What Is Basal Cell Carcinoma?
Basal cell carcinoma (BCC) is a skin cancer that is mainly caused by sun exposure and affects the outer skin layer called the epidermis. It is characterized by a brown scaly patch or white waxy lumps or nodules on the face and neck region. It is the most common cancer in humans, affecting approximately 90 percent of the population.
How Should Sonidegib Be Used?
The drug is available in tablet form to be taken once daily on an empty stomach (one hour before or two hours after the meal). It should be taken around the same time each day. One must follow the prescription label’s directions for taking the drug, and if any part of the information is not understood, one can ask the pharmacist or doctor to explain that part.
The drug should be taken exactly as the doctor prescribes it, and its frequency, duration, and dosage should not be altered without asking the doctor. The doctor may stop or adjust the drug's dose depending on the patient’s response to the medication or in case an individual experiences any side effects.
What Special Precautions Should Be Followed Before Taking Sonidegib?
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Any allergic reaction to Sonidegib, its ingredients, or any other drug should be reported to the doctor.
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One must also tell the doctor about all the prescription and non-prescription drugs one is taking or planning to take, such as nutritional supplements, herbal products, and vitamins.
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The doctor must also know if a person has or ever has any type of muscle disease.
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The doctor should also know if one is breastfeeding, as they might ask the person to stop breastfeeding during the treatment course and also for at least 20 months post-treatment with Sonidegib.
What Are the Side Effects of Sonidegib?
Common Side Effects:
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Diarrhea (watery or loose stool).
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Nausea.
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Itching.
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Hair loss.
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Weight loss.
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Abdominal pain.
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Vomiting.
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Loss of appetite.
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Weakness.
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Pain.
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Tiredness.
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Missed menstrual periods.
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Altered taste sensation.
Serious Side Effects:
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Decreased urination.
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Muscle spasms.
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Inability to urinate.
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Dark-colored urine.
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Muscle pain.
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Muscle tenderness or weakness.
Drug Dosage and Administration
The recommended dosage of Sonidegib is 200 mg (milligrams) taken orally (through the mouth) once a day on an empty stomach at least one hour before a meal or two hours after a meal. The drug is advised to be administered until unacceptable toxicity or disease progression occurs.
Dose Modification:
The drug should be interrupted if;
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Intolerant or severe musculoskeletal adverse reactions occur.
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Initial occurrence of serum creatine kinase (CK) between 2.5 to 10 times ULN (upper limit of normal).
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Recurrent serum creatine kinase levels elevate 2.5 to five times ULN (upper limit of normal).
A daily dose of 200 mg (milligrams) of Sonidegib should be resumed once the clinical symptoms get resolved.
The drug should be permanently discontinued if;
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Renal (kidney) function worsens following serum CK (creatine kinase) elevation greater than 2.5 times ULN (upper limit of normal).
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Serum CK (creatine kinase) elevation is more significant than ten times ULN (upper limit of normal).
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Intolerant or severe musculoskeletal adverse reactions.
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Recurrent serum CK (creatine kinase) elevation is more significant than ten times ULN (upper limit of normal).
Missed Dose
If one misses the dose of Sonidegib, they must take it as soon as they remember. However, if it is already time for the next scheduled dose, one must skip the missed dose and continue with the regular one. Do not take double drug dosage to compensate for the missed one.
Overdose
In case of an overdose from the drug, contact the poison control department. However, if a person collapses, has trouble breathing, or has seizures (an uncontrolled electrical activity in the brain cells), immediately call emergency medical services at 911.
Drug Storage and Disposal
The drug should be stored in an airtight container, away from excess moisture and heat. It should be stored at a controlled room temperature of 22 degrees Celsius (77 degrees Fahrenheit), with excursions permitted to 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit).
Expired, unused, or unneeded medication should be discarded safely by contacting the local garbage or recycling department or contacting the nearest pharmacist to discard the drug through a take-back program. However, one does not have access to a take-back program. In that case, they can discard the medication by following the USFDA guidelines and protocols for safe drug disposal by visiting the website.
For Doctors:
Clinical Pharmacology
Mechanism of Action and Pharmacodynamics
The drug is known to inhibit the Hedgehog pathway (primarily involved in all human cancers) by binding to and blocking smoothened (SMO), a transmembrane protein involved in the signal transduction of Hedgehog. Thus, this mechanism blocks the growth of tumors that depend on this pathway.
Pharmacokinetics
1. Absorption
Under faster conditions, the drug is rapidly absorbed by cancer patients. Following administration, the peak concentration occurs in two to four hours. However, the drug’s total absorption is deficient, approximately six to seven percent.
2. Distribution
Sonidegib's approximate distribution volume is 9166 L (liters). The drug's plasma protein binding is 97 percent, independent of its concentration.
3. Metabolism
The drug gets metabolized through amide hydrolysis and oxidation, and the enzyme responsible is CYP3A (cytochrome P450).
4. Elimination
Based on its pharmacokinetics, the drug's elimination half-life is estimated to be 28 days. The drug is eliminated through the hepatic (liver) route. Around 70 percent and 30 percent of the drug is excreted through feces and urine, respectively.
Ingredients
Active Ingredient: Sonidegib.
Inactive Ingredients: Crospovidone, colloidal silicon dioxide, lactose monohydrate, poloxamer, magnesium stearate, and sodium lauryl sulfate.
Contraindications
The drug is not contraindicated for any condition; however, potential risks and benefits need to be evaluated thoroughly before prescribing the drug to pregnant and breastfeeding women to avoid embryo-fetal toxicity.
Drug Warnings and Precautions:
Embryo-Fetal Toxicity
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Sonidegib can cause severe birth defects or embryo-fetal toxicity when given to pregnant women. Therefore, the drug should be cautiously prescribed to such patients, as it can cause fetotoxic, embryotoxic, and teratogenic effects.
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Females of reproductive potential should be screened for pregnancy before starting treatment with Sonidegib. Females of reproductive potential must be advised to use effective contraception during treatment with the drug and also after 20 months after taking the last drug dosage.
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Also, males of reproductive potential should be advised to use condoms (after vasectomy, which is a surgical procedure to block the sperm from reaching the semen ejaculated from the penis) and protection measures with their female or pregnant partners, as their semen has the potential to cause drug exposure to their sexual partners during treatment and also for at least eight months post-taking the last drug dosage. They must also avoid donating serum, blood products, or blood.
Musculoskeletal Adverse Reactions
The drug can also cause musculoskeletal adverse reactions following elevated serum creatine kinase (CK) levels due to inhibition of the Hedgehog (Hh) pathway. Therefore, doctors must alter or discontinue the drug dosage based on serum creatine kinase elevation to resolve musculoskeletal adverse reactions. Also, doctors should advise the patient to start the recommended drug dosage again after the symptoms of musculoskeletal pain subside. The patient must also be advised to report any new musculoskeletal pain, weakness, or tenderness experienced by the patient during the treatment or when discontinuing the drug.
Drug Interactions
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Diltiazem.
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Efavirenz.
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Modafinil.
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Nefazodone.
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Rifabutin.
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Rifampin.
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Saquinavir.
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Carbamazepine.
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Phenobarbital.
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Phenytoin.
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Telithromycin.
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Atazanavir.
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Fluconazole.
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Erythromycin.
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Itraconazole.
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Ketoconazole.
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Posaconazole.
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Voriconazole.
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Verapamil.
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Clarithromycin.
Clinical Studies:
The safety and effectiveness of Sonidegib have been evaluated in a multicenter, single, multiple cohort, double-blind clinical trial conducted in individuals diagnosed with laBCC or locally advanced basal cell carcinoma (n=194), or mBCC or metastatic basal cell carcinoma (n=36). The individuals were randomized (2:1) to receive either an oral dosage of Sonidegib 800 milligrams or 200 milligrams once a day until intolerable toxicity or disease progression. This randomization was stratified by stage of disease, locally advanced or metastatic, histology (aggressive versus non-aggressive) of laBCC disease, and geographic region.
Individuals with locally advanced basal cell carcinoma were found to have lesions for which radiotherapy was inappropriate (Gorlin syndrome or limitations because of the location of the tumor) or contraindicated that might have recurred after radiotherapy was unresectable or also for which substantial deformity would occur with surgical resection, or that might have recurred after prior surgical resection.
Also, as determined by the blinded central review according to mRECIST (modified response evaluation criteria in solid tumors) for patients with laBCC or RECIST version 1.1 for patients with mBCC, the trial’s major efficacy outcome measure was ORR (objective response rate). Duration of response (DoR), determined by blinded central review, was a key secondary outcome measure.
For individuals with locally advanced basal cell carcinoma, the tumor evaluation response was as per the composite assessment that integrated tumor measurements obtained by digital clinical photography, radiographic assessments of target lesions, and histopathology assessments (through punch biopsies).
All modalities have demonstrated the absence of tumors to achieve a composite evaluation of a complete response. WHO (World Health Organization) also evaluated the response of digital clinical photography using adapted criteria, that is, partial response (PR): greater than or equal to a 50 percent decrease in the sum of the product of perpendicular diameters (SPD) of the lesions, progressive disease (PD): more significant than or equal to 25 percent, increase in the SPD of the lesions, and CR: disappearance of all lesions. Multiple punch biopsies of target lesions were performed to confirm a complete response (CR) or when lesion cyst, ulcerations, scarring, or fibrosis confounded a response assessment.
A total of 66 individuals were randomized to Sonidegib 200 milligrams daily and had locally advanced basal cell carcinoma. Three individuals had a diagnosis of Gorlin syndrome. The demographic characteristics of the 66 individuals locally advanced were: a median age of 67 years (range: 25 to 92 years; 58 percent were greater than or equal to 65 years), 58 percent were male, 89 percent white, and the ECOG performance status of zero was 67 percent. Almost 76 percent of patients had received prior therapy for the treatment of basal cell carcinoma, including radiotherapy (18 percent), surgery (73 percent), and topical pr photodynamic therapies (21 percent). Approximately half of these individuals, or roughly 56 percent, had aggressive histologies.
Use in Specific Populations:
Pregnancy
The drug's mechanism of action and animal reproduction data and studies suggest that the drug can cause harm to the fetus when administered to a pregnant woman. However, the use of this drug in pregnant women is still not established.
In animal reproduction studies, the drug has shown side effects after oral administration at a dose much lower than the recommended human dosage (200 milligrams), thus causing fetotoxicity, embryotoxicity, and teratogenicity.
However, the background risk of miscarriages and birth defects is not known for this population group. Therefore, the drug should be cautiously prescribed to pregnant women after an evaluation of the potential risks and benefits to the fetus.
Breastfeeding
No data shows that the drug is excreted in human milk, the effects on milk production, and the effects on breastfed infants. However, the drug has the potential to cause serious side effects in this population group. Therefore, Sonidegib should not be prescribed to breastfeeding women while taking this drug and for about 20 months after taking the last dose of the drug.
Geriatric Use
The drug's safety and effectiveness have remained the same in this population and young patients. However, to avoid serious adverse effects, dose adjustment or discontinuation of the drug may be required in patients aged 65 and above.
Pediatric Use
The safety and effectiveness of the drug in this population group have not been established yet.
Males and Females of Reproductive Potential
Females of reproductive potential taking Sonidegib are usually advised to use contraception during treatment with the drug and also at least for 20 months after taking the last drug dosage. Also, doctors must verify the pregnancy status of female patients before starting treatment with Sonidegib.
For male patients, it is not known if the drug is present in the semen or not. Also, males should avoid semen donation during the treatment course and for at least eight months after taking the last drug dose.
