On March 18, 2022, the U.S. Food and Drug Administration (FDA) approved Marinus Pharmaceuticals’ Ztalmy® (ganaxolone) oral suspension for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder (CDD) in patients two years of age and older. A rare genetic seizure disorder, CDD is caused by a mutation of the cyclin-dependent kinase-like 5 (CDKL5) gene, located on the X chromosome. Seizures caused by CDD are difficult to control and they can cause severe neuro-developmental impairment. Ztalmy will be supplied as an oral suspension that is taken three times daily. The recommended dose in patients weighing 28kg (about 62 pounds) or less ranges from a starting dose of 6mg/kg three times daily to a maximum dose of 21mg/kg three times daily. For patients weighing over 28kg, the starting dose is 150mg three times daily and the maximum dose is 600mg three times daily. It is expected to be available through one specialty pharmacy beginning in July 2022, following scheduling by the U.S. Drug Enforcement Administration (DEA). The wholesale acquisition cost (WAC) is $2,425 per bottle or approximately $133,000 per patient per year. Here is the prescribing information.

At a Glance

• Brand (Generic) Name: Ztalmy (ganaxolone)
• Manufacturer: Marinus Pharmaceuticals
• Date Approved: March 18, 2022
• Indication: treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients two years of age and older
• Dosage Forms Available: oral suspension: 50mg/mL; each bottle contains 110mL of cherry flavored suspension
• Launch Date: July 2022
• Estimated Annual Cost: $133,000
• CDKL5 mutations cause early-life epilepsy in 1 in 40,000 to 60,000 live births. CDD is an X-linked disorder that affects approximately four times as many females as males. It can cause severe developmental, intellectual and motor disabilities as well as visual impairment.
• Ztalmy, a neuroactive steroid that acts as a positive allosteric modulator of the GABAA receptor, is the first drug approved to treat seizures associated with CDD. Currently available anti-seizure medications typically provide a minimal benefit.
• Approval was based on a Phase 3 study that showed that patients treated with Ztalmy had a 30.7% reduction in 28-day major motor seizure frequency compared to a 6.9% reduction in patients treated with placebo.
• Side effects associated with Ztalmy may include somnolence, fever, salivary hypersecretion and seasonal allergy.
• Ztalmy also being studied for use in other seizure disorders, such as Lennox-Gastaut syndrome and tuberous sclerosis complex.
• Designated as an Orphan Drug, Ztalmy was approved under the FDA’s Priority Review process. Marinus also received a Rare Pediatric Disease Priority Review Voucher, which it plans to sell.

Opdualag (nivolumab/relatlimab-rmbw)

The U.S. Food and Drug Administration (FDA) approved Opdualag™ (nivolumab/relatlimab-rmbw – Bristol Myers Squibb) injection on March 18, 2022. A fixed-dose combination of two immunotherapy drugs, a programmed death receptor-1 (PD-1) blocker that is marketed separately as Opdivo®; and the first in a new therapy class that is known as lymphocyte-activation gene 3 (LAG-3) blockers. Both are antibodies that affect different parts of the body’s immune response. It is indicated to treat melanoma that cannot be removed by surgery or that has metastasized for patients age 12 years and older and who weigh at least 40kg (88 pounds). The recommended dose is two vials (totaling 480mg nivolumab and 160mg of relatlimab) given as a 30-minute intravenous (IV) infusion in a volume of 160mL or more once every four weeks. Adults who weigh less than 40kg can be treated with different doses based on their weight. Pricing, distribution and launch information are not yet available. See prescribing information for Opdualag here.

At a Glance

• Brand (Generic) Name: Opdualag (nivolumab/relatlimab-rmbw) injection
• Manufacturer: Bristol Myers Squibb
• Date Approved: March 18, 2022
• Indication: to treat patients at least 12 years of age who have unresectable or metastatic melanoma
• Dosage Forms Available: single-dose vials containing 240mg of nivolumab and 80mg of relatlimab in 20mL of solution for IV infusion
• Launch Date: Not available
• Estimated Annual Cost: Not available
• Melanoma accounts for about 1% of skin cancers, the most prevalent form of cancer. Typically, easy to treat when in early stages, it involves the uncontrolled production of melanocytes, the cells that cause skin to darken. Unlike other skin cancers, melanoma is more apt to spread into the body. The five-year survival rate for widely metastasized melanoma is only 30%.
• The American Cancer Society estimates that nearly 100,000 new cases of melanoma are diagnosed each year in the U.S. Although just 4% of cases advance into metastases, roughly 7,700 Americans die from melanoma annually. Slightly more common among men than women, it is much more likely among light-skinned individuals, those exposed to high levels of ultraviolet (UV) light and people who have a family history of the disease.
• Both components of Opdualag are immune checkpoint inhibitors – nivolumab enhances the immune system’s ability to attack cancer cells and relatlimab revitalizes T-cell function.
• For patients in the RELATIVITY-047 clinical trial, progression-free survival (PFS) averaged 10.1 months for those receiving Opdualag compared to 4.6 months for participants given only nivolumab.
• Some patients involved in the study experienced immune-related reactions that include serious inflammation of various organs; and/or reactions, such as elevated liver enzymes and fatigue, related to the infusions.
• Currently, immunotherapy with single drugs, including Opdivo and Keytruda® (pembrolizumab) injection is first-line for treating metastatic melanoma. Yervoy® (ipilimumab) injection, a different type of immunotherapy, may be added, as well. For melanoma with specific genetic mutations, a targeted B-Raf Proto-Oncogene (BRAF) inhibitor, such as Zelboraf® (vemurafenib) tablets, a mitogen-activated protein kinase (MEK) inhibitor, such as Mekinist® (trametinib) tablets, is used. Rarely, imatinib or another drug that targets KIT proto-oncogene, receptor tyrosine Kinase (C-KIT) gene mutations are prescribed to treat melanomas that affect unusual parts of the body, including inside the mouth or on the palms of the hands.

Expanded Indication for Lynparza

On March 11, 2022, the U.S. Food and Drug Administration (FDA) approved Lynparza® (olaparib – AstraZeneca) tablets as adjuvant therapy of adult patients who have had treatment with chemotherapy (chemo) either before or after surgery for high-risk deleterious or suspected deleterious gBRCAm human epidermal growth factor receptor 2 (HER2) negative, early breast cancer. In the decisive clinical trial, the chances of recurrent invasive breast cancer, another cancer or death was 42% lower for patients who were taking Lynparza versus those receiving placebo tablets. In the U.S., over 90% of breast cancers are discovered in early stages with between 5% and 10% testing positive for BRCA mutations, according to the American Cancer Society. Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor that has additional FDA indications for some types of ovarian, pancreatic and prostatic cancers that have specific mutations. Recommended dosing for all its indications is 300mg twice each day. Here is updated prescribing information.

New Indication for Rinvoq

AbbVie’s Rinvoq® (upadacitinib) extended-release tablets was approved by the FDA on March 15, 2022, to treat some patients who have ulcerative colitis (UC). It can be used for adults who have active moderate-to-severe UC that has not responded to treatment with at least one tumor necrosis factor (TNF) blocker, such as Humira® (adalimumab). In two clinical studies, symptoms of UC resolved for about one-third of patients treated with Rinvoq as compared with around 5% of patients using placebos after eight weeks. A third trial found that up to 52% of actively treated patients had clinical remissions, with many also able to discontinue corticosteroids, at the one-year mark of maintenance treatment. To treat UC, the recommended dose is 45mg one time per day for eight weeks. Unless UC remains severe, the dose then decreases to 15mg per day for maintenance. Rinvoq, a Janus-Associated kinase (JAK) inhibitor, also has FDA-approved indications for specific patients who have atopic dermatitis (AD), psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Rinvoq should not be taken at the same time as biologic dsease-modifying anti-rheumatic drugs (DMARDs), immunosuppressants or other JAK inhibitors that are being used. A boxed warning is required by the FDA for all JAK inhibitors that are used to treat inflammatory conditions. It cautions that patients taking them may have a greater chance of dying, developing certain cancers, suffering cardiovascular (CV) events, having blood clots and acquiring severe infections. Patients also should be screened for tuberculosis (TB) before starting treatment with a JAK inhibitor and periodically while therapy continues.

FDA Approves Adlarity

A skin patch form of an established oral Alzheimer’s disease (AD) drug was approved by the FDA on March 11, 2022. Corium’s Adlarity® (donepezil transdermal system) is indicated for once-weekly application to the back, buttock or thigh as treatment for all stages of AD-type dementia. Available in boxes containing four 5mg/day or 10mg/day patches, it is expected to be launched early in the autumn of 2022. Donepezil is marketed in oral forms as the brand Aricept® and generics, but many patients who have AD also have trouble swallowing tablets. Some patients experience gastrointestinal (GI) side effects, such as diarrhea, nausea, vomiting and loss of appetite, as well. Skin reactions to the patch may include blisters, redness and swelling. Cost has not yet been released.

Aspruzyo Launched

Following its FDA approval on Feb. 28, 2022, Aspruzyo Sprinkle™ (ranolazine – Sun Pharma) extended-release granules has been introduced to the U.S. market. It is a new dosage form of a drug that has been available as extended-release tablets (Ranexa®/generics) for around 15 years. It treats chronic angina, usually in combination with drugs from other CV therapy classes. The starting dose is 500mg twice a day, which can be increased to no more than 2,000mg/day divided into two doses. Dispensed in cartons containing either 30 or 60 individual packets, Aspruzyo should be mixed with about one tablespoonful of soft, cool food, such as yogurt, and ingested within a few minutes. Cost is not readily available.

Nonprescription Lastacaft Now Available

Allergan has launched a nonprescription version of Lastacaft® (alcaftadine) Ophthalmic Solution 0.25%, which was FDA approved for over-the-counter (OTC) status in December 2021. A once-daily antihistamine eye drop, it is used to prevent itchy eyes due to allergies. Indicated for patients as young as two years old, it begins to work in about three minutes, and relief lasts for roughly 16 hours. The same strength as the prescription version, which is being discontinued, the OTC product now is stocked in retail pharmacies and other stores in 5mL bottles – enough for two months of daily use. Check here for more information.

New Opdivo Indication

Opdivo® (nivolumab – Bristol Myers Squibb) injection, was U.S Food and Drug Administration (FDA) approved for a new indication on March 4, 2022. Now, it is approved for use before surgery is done to remove non-small lung cancer (NSCLC) tumors that are 4cm or larger. It is used in conjunction with chemotherapy (chemo) that includes both a platinum-based agent, such as cisplatin, and another chemo drug, such as paclitaxel. Leading up to surgery, Opdivo is given at 360mg infused intravenously (IV) once every three weeks for one to three doses. Chemo is given on the same schedule and on the same days as Opdivo. Although it is a programmed death receptor-1 (PD-1) inhibitor immunotherapy drug, Opdivo can be used for the new indication whether or not the cancer is positive for PD-L1. In the CheckMate-816 clinical trial, 24.0% of patients using Opdivo and chemo responded to treatment versus only 2.2% of those in the chemo-only group. Event-free survival (EFS) averaged nearly 11 months longer for patients given the combination as for patients receiving only chemo (31.6 months vs 20.8 months, respectively). About one-third of patients getting Opdivo plus chemo had side effects, including constipation, fatigue, nausea and rash; that were severe enough for treatment to be skipped at one or more scheduled times. By itself, Opdivo also is FDA approved to treat some patients who have classical Hodgkin lymphoma, metastatic melanoma, metastatic non-small cell lung cancer (NSCLC), advanced renal cell carcinoma (RCC), urothelial carcinoma or one of numerous other cancers, including some that that are grouped by genetic mutation, not by the affected organ. In combination with another Bristol Myers Squibb drug, Yervoy® (ipilimumab), Opdivo is approved to treat hepatocellular carcinoma (HCC) and several other cancer types. See its complete prescribing information here.

First Generics Launched for Revlimid

In a press release dated on March 7, 2022, Teva Pharmaceuticals disclosed that it has introduced lenalidomide 5mg, 10mg, 15mg and 25mg capsules in the U.S. The first generics for Bristol Myers Squibb’s Revlimid®, the drug is indicated to treat some kinds of myelodysplastic syndrome, to treat mantle cell lymphoma (MCL) after specific previous therapy and to treat multiple myeloma in combination with dexamethasone. Other companies, including Dr. Reddy’s Laboratories, which has 180-day exclusivity for 2.5mg and 20mg capsules; also have FDA approval for lenalidomide capsules. Some companies have reached settlement agreements that delay their launches until future dates, however; and some have agreements to market only small amounts of the generic, gradually ramping up production until the end of January 2026, when restrictions expire along with a key patent on Revlimid. Dose strengths and scheduling depend on the condition being treated. Lenalidomide has a boxed warning and a risk evaluation and mitigation strategy (REMS) due to possibly life-threatening side effects it can have for developing fetuses, as well as for its potential to cause blood cell deficiencies and blood clots. It is dispensed through specialty pharmacies at a price that has not yet been announced. U.S. sales for all strengths of Revlimid were estimated at $9.1 billion for 2021.

Cystadane Generic Available

In February, Oakrum Pharma and its partner, ANI Pharmaceuticals, began distribution for betaine anhydrous powder for oral solution. The first generic for Cystadane® (Ricordati Rare Diseases), it is an Orphan Drug used to treat the rare, inherited condition, homocystinuria (HCU). Patients who have HCU, which affects about one individual per 200,000 to 300,000 in the U.S., cannot digest certain amino acids due to missing or malfunctioning enzymes. New babies are screened for the condition, but some cases are missed and some are diagnosed for older patients. The accumulation of homocysteine in their blood can cause a wide range of symptoms that vary in severity and could include bone abnormalities, cardiovascular disease and learning disorders. To treat it, most patients need to follow a diet that limits protein. Dietary supplements, such as folate and betaine, help to lower blood levels of homocysteine. Betain powder is mixed with four ounces to six ounces of formula, a beverage or soft food and taken twice a day. For children younger than three years old, the starting dose is 50mg/kg, which can be increased by 50mg/kg at weekly intervals until homocysteine levels are controlled. For older children, teens and adults, the typical maintenance dose is 3gm/dose, but some patient may need higher amounts. Generic betaine, which was FDA approved in November 2021, is marketed in bottles containing 180 gm. It has 180 days of exclusivity as a Competitive Generic Therapy (CGT). Pricing information has not been released.

MedWatch Update

Hand Sanitizer

The FDA issued a safety communication for another contaminated hand sanitizer product on March 7, 2022. Tennessee Technical Coatings is recalling all lots of NDC # 76921-0000-01, Hand Sanitizer, isopropyl alcohol 75% in gallon-size containers because it contains methanol. Also known as wood alcohol, methanol is intended for industrial use in products such as pesticides and solvents. It has no medical uses, and it never should be ingested. If it is absorbed through the skin or consumed, methanol can cause dangerous acid buildup in the blood. Immediate symptoms of methanol poisoning can include blurred vision, confusion, dizziness, drowsiness, headache and nausea. Not all individuals exposed to methanol have symptoms, however. Anyone who thinks they may have signs of methanol poisoning or who thinks they may have been exposed to methanol should talk with a doctor right away. Prolonged contact with or consumption of large amounts can lead to serious side effects, such as blindness, coma, seizures and death. Numerous other hand sanitizer brands have been removed from sale in the U.S. due to contamination. Recalled products containing methanol should not be put into the trash or flushed down the drain. Individuals who have them can call the local Poison Control Center or their pharmacy for directions on how to dispose of them. Look here for more information on the latest recall and here for a list of previously recalled products.