Odomzo

Sonidegib is used to treat basal cell carcinoma (BCC; a type of skin cancer) in people with cancer that has come back after surgery or radiation, or in people that cannot be treated with surgery or radiation. Sonidegib is in a class of medications called hedgehog pathway inhibitors. It works by blocking the action of a protein that signals cancer cells to multiply. This helps stop or slow the spread of cancer cells and may help shrink tumors.

Sonidegib comes as a capsule to take by mouth. It is usually taken once a day on an empty stomach, at least 1 hour before or 2 hours after a meal. Take sonidegib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take sonidegib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may need to interrupt or stop your treatment depending on your response to sonidegib and any side effects that you experience.

Talk to your doctor about eating grapefruit and drinking grapefruit juice while taking this medication.

1. Odomzo

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Sonidegib can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have:

• severe or unexplained muscle pain or tenderness (even if this occurs after you have stopped taking sonidegib);
• muscle weakness;
• little or no urinating;
• dark colored urine; or
• fever, unusual tiredness.

Common side effects may include:

• stomach pain, nausea, vomiting, diarrhea;
• loss of appetite, weight loss;
• muscle spasms;
• headache;
• missed menstrual periods;
• itchy skin, hair loss; or
• changes in your sense of taste.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Mechanism Of Action

Sonidegib is an inhibitor of the Hedgehog pathway. Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction.

Pharmacodynamics

At a dose of 800 mg once daily, sonidegib does not prolong the QTc interval.

Pharmacokinetics

Less than 10% of an oral dose of ODOMZO is absorbed. Following the administration of a single ODOMZO dose (100 mg to 3000 mg) under fasted conditions in patients with cancer, the median time-to-peak concentration (Tmax) was 2 to 4 hours. Sonidegib exhibited dose-proportional increases in the area under the curve (AUC) and the maximal concentration (Cmax) over the dose range of 100 mg to 400 mg, but less than dose-proportional increases at doses greater than 400 mg. Steady-state was reached approximately 4 months after starting ODOMZO and the estimated accumulation at steady-state was 19-fold. Following a dose of 200 mg once daily, the estimated mean steady-state Cmax is 1030 ng/mL, AUC0-24h is 22 μg*h/mL and minimal concentration (Cmin) is 890 ng/mL.

A high-fat meal (approximately 1000 calories with 50% of calories from fat) increased exposure to sonidegib (geometric mean AUCinf and Cmax) by 7.4-to 7.8-fold [see DOSAGE AND ADMINISTRATION].

The estimated apparent steady-state volume of distribution (Vss/F) was 9,166 L. Sonidegib was greater than 97% bound to human plasma proteins in vitro and the binding was concentration independent. In vitro studies suggested that sonidegib is not a substrate of P-glycoprotein, MRP2 or BCRP.

The elimination half-life (t½) of sonidegib estimated from population pharmacokinetic (PK) modeling was approximately 28 days.

Metabolism

Sonidegib is primarily metabolized by CYP3A. The main circulating compound was unchanged sonidegib (36% of circulating radioactivity).

Excretion

Sonidegib and its metabolites are eliminated primarily by the hepatic route. Of the absorbed dose, approximately 70% was eliminated in the feces and 30% was eliminated in the urine. Unchanged sonidegib was not detectable in the urine.

Specific Populations

Mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment had no clinically meaningful effect on sonidegib exposure as compared to subjects with normal hepatic function.

Mild (CLcr 60 to 89 mL/min) and moderate (CLcr 30 to 59 mL/min) renal impairment had no effect on sonidegib steady-state exposure as compared to patients with normal renal function (CLcr ≥ 90 mL/min).

Age, body weight, or sex had no clinically meaningful effect on sonidegib steady-state exposure.

A cross study comparison suggests that geometric mean AUCinf of sonidegib is 1.7-fold higher in Japanese healthy subjects compared to Western healthy subjects (Whites and Blacks) following a single 200 mg dose of ODOMZO.

Drug Interaction Studies

Strong CYP3A inhibitor: The geometric mean sonidegib AUC0-10d increased by 2.2-fold and the Cmax increased by 1.5fold when ODOMZO at a dose of 800 mg was taken with ketoconazole compared to ODOMZO alone [see DRUG INTERACTIONS]. The geometric mean sonidegib steady-state AUC0-24h would similarly increase in cancer patients taking ODOMZO 200 mg once daily when coadministered with a strong CYP3A inhibitor for 14 days.

Moderate CYP3A inhibitor: The geometric mean sonidegib steady-state AUC0-24h would increase 1.8-fold when ODOMZO 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 14 days and would increase 2.8-fold when ODOMZO 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 4 months.

Strong CYP3A inducer: The geometric mean sonidegib AUC0-10d decreased by 72% and the Cmax decreased by 54% when ODOMZO at a dose of 800 mg was taken with rifampicin compared to ODOMZO alone [see DRUG INTERACTIONS].

Moderate CYP3A inducer: The geometric mean sonidegib steady-state AUC0-24h would decrease 56% in cancer patients taking ODOMZO 200 mg once daily when coadministered with a moderate CYP3A inducer (efavirenz) for 14 days and would decrease 69% when coadministered with a moderate CYP3A inducer (efavirenz) for 4 months [see DRUG INTERACTIONS].

In vitro studies suggested that sonidegib inhibits CYP2B6 and CYP2C9 and it does not induce CYP1A2, CYP2B6 or CYP3A expression or activity.

In vitro studies suggested that sonidegib inhibits BCRP, but not P-glycoprotein, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2.

No clinically meaningful effect on sonidegib exposure was observed when ODOMZO at dose of 200 mg was coadministered with esomeprazole, a proton pump inhibitor.

Animal Toxicology And/Or Pharmacology

Body tremors along with significant increases in creatine kinase were observed in rats administered oral sonidegib for 13 weeks or longer at ≥ 10 mg/kg/day (approximately ≥ 2 times the recommended human dose based on AUC).

Clinical Studies

The safety and effectiveness of ODOMZO were evaluated in a single, multicenter, double-blind, multiple cohort clinical trial conducted in patients with locally advanced basal cell carcinoma (laBCC) (n=194) or metastatic basal cell carcinoma (mBCC) (n=36) (Study 1). Patients were randomized (2:1) to receive either ODOMZO 800 mg or 200 mg orally, once daily, until disease progression or intolerable toxicity. Randomization was stratified by stage of disease (locally advanced or metastatic), laBCC disease histology (aggressive vs. non-aggressive), and geographic region. Patients with laBCC were required to have lesions for which radiotherapy was contraindicated or inappropriate (e.g., Gorlin syndrome or limitations because of location of tumor), that had recurred after radiotherapy, that were unresectable or for which surgical resection would result in substantial deformity, or that had recurred after prior surgical resection.

The major efficacy outcome measure of the trial was objective response rate (ORR) as determined by blinded central review according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) for patients with laBCC or RECIST version 1.1 for patients with mBCC. Duration of response (DoR), determined by blinded central review, was a key secondary outcome measure.

For patients with laBCC, the evaluation of tumor response was based on a composite assessment that integrated tumor measurements obtained by radiographic assessments of target lesions (per RECIST 1.1), digital clinical photography, and histopathology assessments (via punch biopsies). All modalities used must have demonstrated absence of tumor to achieve a composite assessment of complete response (CR). Response by digital clinical photography was evaluated by World Health Organization (WHO) adapted criteria [partial response (PR): ≥ 50% decrease in the sum of the product of perpendicular diameters (SPD) of the lesions, CR: disappearance of all lesions, progressive disease (PD): ≥ 25% increase in the SPD of the lesions]. Multiple punch biopsies of target lesions were performed to confirm a CR or when a response assessment was confounded by presence of lesion ulceration, cyst, and or scarring/fibrosis.

A total of 66 patients randomized to ODOMZO 200 mg daily had laBCC. Three of these patients had a diagnosis of Gorlin Syndrome. The demographic characteristics of the 66 patients with laBCC were: median age of 67 years (range: 25 to 92 years; 58% were ≥ 65 years); 58% male, 89% white, and ECOG performance status of 0 (67%). Seventy-six percent of patients had prior therapy for treatment of BCC; this included surgery (73%), radiotherapy (18%), and topical/photodynamic therapies (21%). Approximately half of these patients (56%) had aggressive histology.

Patients with laBCC randomized to receive ODOMZO 200 mg daily were followed for at least 12 months unless discontinued earlier. The ORR was 58% (95% confidence interval: 45, 70), consisting of 3 (5%) complete responses and 35 (53%) partial responses. A pre-specified sensitivity analysis using an alternative definition for complete response, defined as at least a PR according to MRI and/or photography and no evidence of tumor on biopsy of the residual lesion, yielded a CR rate of 20%. Among the 38 patients with an objective response, 7 (18%) patients experienced subsequent disease progression with 4 of these 7 patients having maintained a response of 6 months or longer. The remaining 31 patients (82%) have ongoing responses ranging from to 1.9+ to 18.6+ months and the median duration of response has not been reached.

A total of 128 patients randomized to ODOMZO 800 mg daily had laBCC. Twelve of these patients had a diagnosis of Gorlin Syndrome. There was no evidence of better antitumor activity (ORR) among patients with laBCC randomized to receive ODOMZO 800 mg daily and followed for at least 12 months unless discontinued earlier.

ODOMZO®
(o-DOM-zo)
(sonidegib) Capsules

What is the most important information I should know about ODOMZO?

ODOMZO can cause your baby to die before it is born (be stillborn) or cause your baby to have severe birth defects.

For females who can become pregnant:

• You should talk to your healthcare provider about the risks of ODOMZO to your unborn child.
• Your healthcare provider will do a pregnancy test before you start taking ODOMZO.
• In order to avoid pregnancy, you should use birth control during treatment, and for at least 20 months after your final dose of ODOMZO. Talk to your healthcare provider about what birth control method is right for you during this time.
• Talk to your healthcare provider right away if you have unprotected sex or if you think your birth control has failed.
• Tell your healthcare provider right away if you become pregnant or think that you may be pregnant.

For males:

• It is not known if ODOMZO is present in semen. Do not donate semen while you are taking ODOMZO and for at least 8 months after your final dose.
• You should always use a condom, even if you have had a vasectomy, during sex with female partners who are pregnant or who are able to become pregnant, during treatment with ODOMZO and for at least 8 months after your final dose to protect your female partner from being exposed to ODOMZO.
• Tell your healthcare provider right away if your partner becomes pregnant or thinks she is pregnant while you are taking ODOMZO.

Exposure to ODOMZO during pregnancy:

If you think that you or your female partner may have been exposed to ODOMZO during pregnancy, talk to your healthcare provider right away. If you become pregnant during treatment with ODOMZO, you or your healthcare provider should report your pregnancy to Novartis Pharmaceuticals Corporation at 1-888-669-6682.

What is ODOMZO?

ODOMZO is a prescription medicine used to treat adults with a type of skin cancer, called basal cell carcinoma, that has come back following surgery or radiation or that cannot be treated with surgery or radiation.

It is not known if ODOMZO is safe and effective in children.

What should I tell my healthcare provider before taking ODOMZO?

Before you take ODOMZO, tell your healthcare provider if you:

• have muscle pain or spasms, or have a history of a muscle disorder called rhabdomyolysis or myopathy
• have any other medical conditions
• are pregnant or plan to become pregnant. See “What is the most important information I should know about ODOMZO?”
• are breastfeeding or plan to breastfeed. It is not known if ODOMZO passes into your breast milk. Do not breastfeed during treatment and for 20 months after your final dose of ODOMZO. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take ODOMZO?

• Take ODOMZO exactly as your healthcare provider tells you.
• Take ODOMZO 1 time each day.
• Take ODOMZO at least 1 hour before or 2 hours after a meal.
• If you miss a dose, skip the missed dose. Take your next dose as scheduled.

What should I avoid while taking ODOMZO?

• Do not donate blood or blood products while you are taking ODOMZO and for 20 months after your final dose.
• Do not donate semen while taking ODOMZO and for at least 8 months after your final dose.

What are possible side effects of ODOMZO?

ODOMZO can cause serious side effects, including:

• See “What is the most important information I should know about ODOMZO?”
• Muscle Problems. Muscle spasms and muscle pain are common with ODOMZO, but can also sometimes be symptoms of serious muscle problems. ODOMZO can increase your risk of muscle pain and, rarely a serious condition caused by injury to the muscles (rhabdomyolysis) that can lead to kidney damage. Tell your healthcare provider right away if you develop any new or worsening muscle spasms, pain or tenderness, dark urine, or decreased amount of urine during treatment with ODOMZO.
  Your healthcare provider should do a blood test to check for muscle problems and to check your kidney function before you start taking ODOMZO, during treatment, and if you develop muscle problems.

The most common side effects of ODOMZO include:

• hair loss
• change in taste
• tiredness
• nausea
• diarrhea
• weight loss
• decreased appetite
• vomiting
• stomach area (abdominal) pain
• itching
• headache

ODOMZO can cause absence of menstrual periods (amenorrhea) in females who are able to become pregnant. It is not known if amenorrhea is permanent. Talk to your healthcare provider if you have concerns about fertility.

These are not all of the possible side effects of ODOMZO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ODOMZO?

• Store ODOMZO at room temperature between 68°F to 77°F (20°C to 25°C).

Keep ODOMZO and all medicines out of the reach of children.

General information about the safe and effective use of ODOMZO

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ODOMZO for a condition for which it was not prescribed. Do not give ODOMZO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ODOMZO that is written for health professionals.

What are the ingredients in ODOMZO?

Active ingredient: sonidegib

Inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, poloxamer, and sodium lauryl sulfate. The capsule shell contains gelatin, red iron oxide, and titanium dioxide. The black printing ink contains ammonium hydroxide, black iron oxide, propylene glycol, and shellac.

Odomzo is a prescription medication used to treat basal cell carcinoma, a type of skin cancer.

Odomzo belongs to a group of drugs called selective smoothened (SMO) inhibitors. These help to regulate tissue repair. 

This medication comes in capsule form. It is taken once daily taken on an empty stomach, at least 1 hour before or 2 hours after a meal. 

Common side effects include muscle spasms, hair loss, and change in sense of taste.

Odomzo can also cause tiredness. Do not drive or operate heavy machinery until you know how this medication will affect you.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Odomzo is excreted in human breast milk or if it will harm your nursing baby. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Odomzo, nursing is not recommended. Do not breastfeed during treatment and for 20 months after your final dose of Odomzo.

Talk to your healthcare provider about the best way to feed your baby during this time.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of sonidegib in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of sonidegib in the elderly. However, elderly patients are more likely to have unwanted effects, which may require caution in patients receiving sonidegib.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aprepitant
• Atazanavir
• Boceprevir
• Carbamazepine
• Clarithromycin
• Conivaptan
• Diltiazem
• Dronedarone
• Efavirenz
• Erythromycin
• Fluconazole
• Fosaprepitant
• Fosphenytoin
• Imatinib
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir
• Modafinil
• Nefazodone
• Nelfinavir
• Netupitant
• Phenobarbital
• Phenytoin
• Posaconazole
• Rifabutin
• Rifampin
• Ritonavir
• Saquinavir
• St John's Wort
• Telaprevir
• Telithromycin
• Verapamil
• Voriconazole

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Myopathy (muscle problem), history of or
• Rhabdomyolysis (muscle problem), history of—Use with caution. May increase risk for more serious side effects.

• It is used to treat skin cancer.

     Recommended Dosing

The recommended dose of Odomzo is 200 mg taken orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal, administered until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)].

Verify the pregnancy status of females of reproductive potential prior to initiating Odomzo. Obtain serum creatine kinase (CK) levels and renal function tests prior to initiating Odomzo in all patients [see Dosage and Administration (2.2) and Warnings and Precautions (5.2)].

If a dose of Odomzo is missed, resume dosing with the next scheduled dose.

     Dose Modifications

Interrupt Odomzo for

• Severe or intolerable musculoskeletal adverse reactions.
• First occurrence of serum CK elevation between 2.5 and 10 times upper limit of normal (ULN).
• Recurrent serum CK elevation between 2.5 and 5 times ULN.

Resume Odomzo at 200 mg daily upon resolution of clinical signs and symptoms.

Permanently discontinue Odomzo for

• Serum CK elevation greater than 2.5 times ULN with worsening renal function.
• Serum CK elevation greater than 10 times ULN.
• Recurrent serum CK elevation greater than 5 times ULN.
• Recurrent severe or intolerable musculoskeletal adverse reactions.

200 mg opaque pink colored capsules with ‘SONIDEGIB 200MG’ printed on the body and ‘NVR’ printed on the cap in black ink (equivalent to 281 mg of diphosphate salt of sonidegib).

     Effects of Other Drugs on Sonidegib

Strong and Moderate CYP3A Inhibitors

Avoid concomitant administration of Odomzo with strong CYP3A inhibitors, including but not limited to saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone [see Clinical Pharmacology (12.3)].

Avoid concomitant administration of Odomzo with moderate CYP3A inhibitors, including but not limited to atazanavir, diltiazem, and fluconazole. If a moderate CYP3A inhibitor must be used, administer the moderate CYP3A inhibitor for less than 14 days and monitor closely for adverse reactions particularly musculoskeletal adverse reactions [see Clinical Pharmacology (12.3)].

Strong and Moderate CYP3A Inducers

Avoid concomitant administration of Odomzo with strong and moderate CYP3A inducers, including but not limited to carbamazepine, efavirenz, modafinil, phenobarbital, phenytoin, rifabutin, rifampin and St. John’s Wort (Hypericum perforatum) [see Clinical Pharmacology (12.3)].

Take Odomzo exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Your doctor will perform blood tests to make sure you do not have conditions that would prevent you from safely using this medicine.

Take Odomzo on an empty stomach, at least 1 hour before or 2 hours after a meal.

You will need frequent medical tests to be sure this medicine is not causing harmful effects. Your cancer treatments may be delayed based on the results of these tests.

Store Odomzo at room temperature away from moisture and heat.