Updates from FDA
APhA Staff
New drugs
AVUTOMETINIB CAPSULES AND DEFACTINIB TABLETS CO-PACKAGED
(Avmapki Fakzynja Co-Pack—Verastem Oncology)
Drug class: Avutometinib and defactinib are both kinase inhibitors.
Indication: Avmapki Fakzynja Co-Pack is indicated for the treatment of adult patients with KRAS-mutated recurrent low-grade serous ovarian cancer who have received prior systemic therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent on verification and description of clinical benefit in a confirmatory trial.
Recommended dosage and administration: A 3.2 mg dose of Avmapki is administered orally twice weekly (day 1 and day 4) for the first 3 weeks of each 4-week cycle. A 200 mg dose of Fakzynja is administered twice daily for the first 3 weeks of each 4-week cycle.
Common adverse effects: The most common adverse reactions are increased creatine phosphokinase, nausea, fatigue, increased aspartate aminotransferase, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased alanine aminotransferase, vomiting, increased blood bilirubin, increased triglycerides, decreased lymphocyte count, abdominal pain, dyspepsia, dermatitis acneiform, vitreoretinal disorders, increased alkaline phosphatase, stomatitis, pruritus, visual impairment, decreased platelet count, constipation, dry skin, dyspnea, cough, UTI, and decreased neutrophil count.
Warnings and precautions: Ocular toxicities, including visual impairment and vitreoretinal disorders have occurred. Perform comprehensive ophthalmic evaluation at baseline, prior to cycle 2, every 3 cycles thereafter, and as clinically indicated. Withhold the medication for ocular toxicities until improvement at the same or reduced dose. Permanently discontinue for any grade 4 toxicity. Monitor for skin toxicities and interrupt, reduce, or permanently discontinue Avmapki Fakzynja Co-Pack based on severity, tolerability, and duration. Monitor liver function tests prior to each cycle, on day 15 of the first 4 cycles, and as clinically indicated. Withhold, reduce, or discontinue based on severity and persistence of abnormality. Monitor creatine phosphokinase prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. If increased creatine phosphokinase occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce, or permanently discontinue Avmapki Fakzynja Co-Pack based on severity and duration of the adverse reaction.
Avmapki Fakzynja Co-Pack can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. Avoid concomitant use with strong and moderate CYP3A4 inhibitors and inducers. Avoid concomitant use with warfarin and gastric acid–reducing agents. If use of an acid-reducing agent cannot be avoided, administer Fakzynja 2 hours before or 2 hours after the administration of a locally acting antacid. Advise patients not to breastfeed. Avmapki Fakzynja Co-Pack may impair fertility in males and females.
ACOLTREMON OPHTHALMIC SOLUTION
(Tryptyr—Alcon Labs)
Drug class: Tryptyr is a TRPM8 thermoreceptor agonist.
Indication: Tryptyr is indicated for the treatment of the signs and symptoms of dry eye disease.
Recommended dosage and administration: Instill one drop in each eye twice daily, approximately 12 hours apart.
Common adverse effects: The most common adverse reaction is instillation site pain.
Warnings and precautions: To avoid the potential for eye injury and contamination, do not touch the vial tip to the eye or other surfaces.
New dosage forms
HYDROCORTISONE ORAL SOLUTION
(Khindivi—Eton Pharmaceuticals)
Drug class: Khindivi is a corticosteroid.
Indication: Khindivi is indicated as replacement therapy in pediatric patients 5 years and older with adrenocortical insufficiency. Khindivi is not approved for increased dosing during periods of stress or acute events. Use a different hydrocortisone-containing drug product for stress dosing.
Recommended dosage and administration: Individualize the dose, using the lowest dosage possible. The recommended starting dosage of Khindivi is 8 to 10 mg/m2 daily. Higher doses may be needed based on the patient’s age and symptoms of the disease. Use of lower starting doses may be sufficient in patients with residual but decreased endogenous cortisol production. Divide the total daily dose into three doses and administer three times daily. Older patients may have their dose divided by two and administered twice daily. Khindivi contains the inactive ingredients polyethylene glycol 400, propylene glycol, and glycerin. If patients experience adverse reactions, such as hyperosmolarity, metabolic acidosis, hypoglycemia, hepato-renal injury, central nervous system toxicity, and GI adverse effects, consider discontinuation of Khindivi and switch to another hydrocortisone product. When switching from other oral hydrocortisone formulations, use the same total daily hydrocortisone dosage. If symptoms of adrenal insufficiency occur, increase the total daily dosage.
Common adverse effects: The most common adverse reactions include fluid retention, alteration in glucose tolerance, elevation in BP, behavioral and mood changes, increased appetite, and weight gain.
Warnings and precautions: Khindivi is contraindicated in hypersensitivity to hydrocortisone or any component of Khindivi. Undertreatment, sudden discontinuation of therapy, or switching from another oral hydrocortisone formulation may lead to adrenocortical insufficiency, adrenal crisis, and death. Adrenal crisis may also be induced by stress events such as infections or surgery. During periods of stress, switch to another oral hydrocortisone product and increase the dose. Switch patients who are vomiting, severely ill, or unable to take oral medications to parenteral corticosteroid formulations. Use of a greater than replacement dosage can suppress the immune system and increase the risks of new infections or exacerbation of latent infections with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic infections.
Monitor for signs and symptoms of infections. Long-term use in excessive doses may cause growth retardation. Use the minimum dosage of Khindivi to achieve the desired clinical response and monitor the patient’s growth. Prolonged use with supraphysiologic doses may cause Cushing’s syndrome. Monitor patients for signs and symptoms of Cushing’s syndrome every 6 months. Corticosteroids decrease bone formation and increase bone resorption, which may lead to inhibition of bone growth and development of osteoporosis. Use may be associated with severe psychiatric adverse reactions such as euphoria, mania, and psychosis with hallucinations, delirium, or depression. Symptoms typically emerge within a few days or weeks of starting the treatment. Most reactions resolve after either dose reduction or withdrawal, although specific treatment may be necessary. Monitor patients for behavioral and mood disturbances during treatment. Instruct caregivers and patients to seek medical advice if psychiatric symptoms develop.
Cataracts, glaucoma, and central serious chorioretinopathy have been reported with prolonged use of high doses. Monitor patients for blurred vision or other visual disturbances and, if they occur, refer them to an ophthalmologist. There is an increased risk for GI adverse reactions in patients with certain GI disorders. Concomitant administration with CYP3A4 inhibitors may require a decrease in the Khindivi dose. Concomitant administration with CYP3A4 inducers, estrogen, or estrogen-containing products may require an increase in the Khindivi dose. Excessive doses of Khindivi may increase blood glucose concentrations and dose adjustments for antidiabetic agents may be required. Concomitant administration with NSAIDs increases the risk of GI adverse reactions.
New combinations
TELMISARTAN, AMLODIPINE, AND INDAPAMIDE
(Widaplik—George Medicines)
Drug class: Widaplik is a combination tablet of telmisartan, an angiotensin II receptor blocker, amlodipine, a dihydropyridine calcium channel blocker, and indapamide, a thiazide-like diuretic.
Indication: Widaplik is indicated for the treatment of hypertension, including as initial treatment, to lower BP. Lowering BP reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
Recommended dosage and administration: For initial treatment of hypertension, start with Widaplik 10 mg/1.25 mg/0.625 mg or Widaplik 20 mg/2.5 mg/1.25 mg orally once daily. Titrate up to maximum dose of Widaplik 40 mg/5 mg/2.5 mg orally once daily. Dosage may be increased after 2 weeks to the maximum dosage to achieve more rapid control. Almost all of the antihypertensive effect is apparent within 2 weeks of initiating treatment.
Common adverse effects: The most common adverse reaction is symptomatic hypotension. Low sodium and potassium values were recorded more often with Widaplik than with placebo.
Boxed warning: When pregnancy is detected, discontinue Widaplik as soon as possible. Drugs that act directly on the renin-angiotensin-aldosterone system can cause injury and death to the developing fetus.
Other warnings and precautions: Widaplik is contraindicated in anuria and patients with a known hypersensitivity to telmisartan, amlodipine, indapamide, or to other sulfonamide-derived drugs, or to any other component of this product. Do not administer aliskiren with Widaplik in patients with diabetes. Correct volume depletion prior to initiation of Widaplik. Monitor serum electrolytes and glucose. Impaired renal function may occur. Acute angle closure glaucoma can develop. Hyperuricemia may occur. There is an increased risk of renal impairment and loss of antihypertensive effect if used concomitantly with NSAIDs. If simvastatin is coadministered with Widaplik, do not exceed doses greater than 20 mg daily of simvastatin. Breastfeeding is not recommended during treatment. Severe cases of hyponatremia, accompanied by hypokalemia have been reported with use of indapamide in older females. Consider initiation at lower doses for patients 65 years and older. In patients with hepatic impairment, monitor carefully and start treatment at low doses. ■