Side Effects of Opdivo (nivolumab)

Opdivo (nivolumab) is a chemotherapy drug used to treat skin cancer (melanoma) and many different kinds of metastatic cancer, such as lung cancer, a type of kidney cancer, Hodgkin lymphoma, types of head and neck cancer, bladder cancer, types of liver cancer, and types of colorectal cancer.

No formal drug interaction studies have been conducted with Opdivo. 

Based on its mechanism of action and data from animal studies, Opdivo can cause fetal harm when administered to a pregnant woman. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, Opdivo has the potential to be transmitted from the mother to the developing fetus. The effects of Opdivo are likely to be greater during the second and third trimesters of pregnancy.

It is unknown if Opdivo is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Opdivo, women are advised to discontinue breastfeeding during treatment with Opdivo.

WARNING

• Orkambi should be used with caution in patients with advanced liver disease and only when the benefits are expected to outweigh the risks.
• Orkambi is associated with liver-related adverse events. Liver function should be tested before treatment and every 3 months during the first year of treatment, and yearly thereafter.
• Chest discomfort, dyspnea, and abnormal respiration may occur.
• Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ivacaftor. Baseline and follow-up eye examinations are recommended in pediatric patients treated with Orkambi.

What are the common side effects of Opdivo?

Common side effects Opdivo of include

• feeling tired,
• pain in muscles/bones/joints,
• diarrhea,
• weakness,
• shortness of breath,
• decreased appetite,
• upper respiratory tract infection,
• headache,
• rash,
• itchy skin,
• nausea,
• cough,
• constipation,
• back pain,
• fever, and
• stomach pain.

What are the serious side effects of Opdivo?

Serious side effects of Opdivo include

• severe infusion reactions (chills or shaking, itching or rash, flushing, difficulty breathing, dizziness, fever, and feeling like passing out) and
• complications of stem cell transplant that uses donor stem cells (allogeneic) after treatment with Opdivo. 

Potential For Other Drugs To Affect Lumacaftor/Ivacaftor

Inhibitors Of CYP3A

Co-administration of lumacaftor/ivacaftor with itraconazole, a strong CYP3A inhibitor, did not impact the exposure of lumacaftor, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours (the approved dose of ivacaftor monotherapy).

Therefore, no dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking Orkambi. However, when initiating Orkambi in patients taking strong CYP3A inhibitors, reduce the Orkambi dose to 1 tablet daily or 1 packet of oral granules every other day (patients aged 2 through 5 years) for the first week of treatment to allow for the steady-state induction effect of lumacaftor. Following this period, continue with the recommended daily dose.

Examples of strong CYP3A inhibitors include:

• ketoconazole, itraconazole, posaconazole, and voriconazole
• telithromycin, clarithromycin.

No dose adjustment is recommended when used with moderate or weak CYP3A inhibitors.

Inducers Of CYP3A

Co-administration of lumacaftor/ivacaftor with rifampin, a strong CYP3A inducer, had minimal effect on the exposure of lumacaftor, but decreased ivacaftor exposure (AUC) by 57%. This may reduce the effectiveness of Orkambi.

Therefore, co-administration with strong CYP3A inducers, such as

• rifampin,
• rifabutin,
• phenobarbital,
• carbamazepine,
• phenytoin, and
• St. John's wort (Hypericum perforatum), is not recommended.

No dose adjustment is recommended when used with moderate or weak CYP3A inducers.

Potential For Lumacaftor/Ivacaftor To Affect Other Drugs

CYP3A Substrates

Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by approximately 80%. Administration of Orkambi may decrease systemic exposure of medicinal products which are substrates of CYP3A, thereby decreasing the therapeutic effect of the medicinal product.

Co-administration of Orkambi is not recommended with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index such as:

• Benzodiazepines: midazolam, triazolam (consider an alternative to these benzodiazepines).
• Immunosuppressants: cyclosporine, everolimus, sirolimus, and tacrolimus (avoid the use of Orkambi).

CYP2B6 And CYP2C Substrates

In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. Additionally, in vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of Orkambi with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates.

Digoxin And Other P-gp Substrates

Based on in vitro results which showed P-gp inhibition and pregnane-X-receptor (PXR) activation, lumacaftor has the potential to both inhibit and induce P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of Orkambi with P-gp substrates may alter the exposure of these substrates.

Monitor the serum concentration of digoxin and titrate the digoxin dose to obtain the desired clinical effect.

Anti-allergics And Systemic Corticosteroids

Orkambi may decrease the exposure of montelukast, which may reduce its efficacy. No dose adjustment for montelukast is recommended. Employ appropriate clinical monitoring, as is reasonable, when co-administered with Orkambi.

Concomitant use of Orkambi may reduce the exposure and effectiveness of prednisone and methylprednisolone. A higher dose of these systemic corticosteroids may be required to obtain the desired clinical effect.

Antibiotics

Concomitant use of Orkambi may decrease the exposure of clarithromycin, erythromycin, and telithromycin, which may reduce the effectiveness of these antibiotics. Consider an alternative to these antibiotics, such as ciprofloxacin, azithromycin, and levofloxacin.

Antifungals

Concomitant use of Orkambi may reduce the exposure and effectiveness of itraconazole, ketoconazole, posaconazole, and voriconazole. Concomitant use of Orkambi with these antifungals is not recommended. Monitor patients closely for breakthrough fungal infections if such drugs are necessary. Consider an alternative such as fluconazole.

Anti-inflammatories

Concomitant use of Orkambi may reduce the exposure and effectiveness of ibuprofen. A higher dose of ibuprofen may be required to obtain the desired clinical effect.

Antidepressants

Concomitant use of Orkambi may reduce the exposure and effectiveness of citalopram, escitalopram, and sertraline. A higher dose of these antidepressants may be required to obtain the desired clinical effect.

Hormonal Contraceptives

Orkambi may decrease hormonal contraceptive exposure, reducing the effectiveness. Hormonal contraceptives, including oral, injectable, transdermal, and implantable, should not be relied upon as an effective method of contraception when co-administered with Orkambi.

Concomitant use of Orkambi with hormonal contraceptives increased the menstrual abnormality events. Avoid concomitant use unless the benefit outweighs the risks.

Oral Hypoglycemics

Concomitant use of Orkambi may reduce the exposure and effectiveness of repaglinide, and may alter the exposure of sulfonylurea. A dose adjustment may be required to obtain the desired clinical effect. No dose adjustment is recommended for metformin.

Proton Pump Inhibitors, H2 Blockers, Antacids

Orkambi may reduce the exposure and effectiveness of proton pump inhibitors such as omeprazole, esomeprazole, and lansoprazole, and may alter the exposure of ranitidine. A dose adjustment may be required to obtain the desired clinical effect. No dose adjustment is recommended for calcium carbonate antacid.

Warfarin

Orkambi may alter the exposure of warfarin. Monitor the international normalized ratio (INR) when warfarin co-administration with Orkambi is required.

Concomitant Drugs That Do Not Need Dose Adjustment

No dosage adjustment of Orkambi or concomitant drug is recommended when Orkambi is given with the following:

• azithromycin,
• aztreonam,
• budesonide,
• ceftazidime,
• cetirizine,
• ciprofloxacin,
• colistimethate,
• colistin,
• dornase alfa,
• fluticasone,
• ipratropium,
• levofloxacin,
• pancreatin,
• pancrelipase,
• salbutamol,
• salmeterol,
• sulfamethoxazole and
• trimethoprim, tiotropium, and tobramycin.

Based on the metabolism and route of elimination, Orkambi is not expected to impact the exposure of these drugs.

The following adverse reactions are discussed in greater detail in other sections of the label:

• Use in Patients with Advanced Liver Disease
• Liver-related Events
• Respiratory Events
• Effect on Blood Pressure

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The overall safety profile of Orkambi is based on the pooled data from 1108 patients with CF 12 years and older who are homozygous for the F508del mutation in the CFTR gene and who received at least one dose of study drug in 2 double-blind, placebo-controlled, Phase 3 clinical trials, each with 24 weeks of treatment (Trials 1 and 2).

In addition, the following clinical trials have been conducted:

• A 24-week open-label trial (Trial 3) in 58 patients with CF aged 6 through 11 years homozygous for the F508del-CFTR mutation.
• A 24-week, placebo-controlled trial (Trial 4) in 204 patients aged 6 through 11 years homozygous for the F508del-CFTR mutation.
• A 24-week, open label trial (Trial 5) in 46 patients aged 12 years and older homozygous for the F508del-CFTR mutation and with advanced lung disease (ppFEV₁ <40).
• A 24-week, open-label trial (Trial 6) in 60 patients aged 2 through 5 years homozygous for the F508del-CFTR mutation.

Of the 1108 patients, in the pooled analyses of Trial 1 and Trial 2, 49% were female and 99% were Caucasian; 369 patients received Orkambi every 12 hours and 370 received placebo.

The proportion of patients who prematurely discontinued study drug due to adverse events was 5% for patients treated with Orkambi and 2% for patients who received placebo.

Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with Orkambi included

• pneumonia,
• hemoptysis,
• cough,
• increased blood creatine phosphokinase, and
• transaminase elevations.

These occurred in 1% or less of patients.

Table 3 shows adverse reactions occurring in ≥5% of patients with CF ages 12 years and older treated with Orkambi who are homozygous for the F508del mutation in the CFTR gene that also occurred at a higher rate than in patients who received placebo in the two double-blind, placebo-controlled trials.

Table 3: Incidence of Adverse Drug Reactions in ≥5% of Orkambi-Treated Patients Ages 12 Years and Older Who are Homozygous for the F508del Mutation in the CFTR Gene in 2 Placebo-Controlled Phase 3 Clinical Trials of 24 Weeks Duration

The safety profile from two pediatric trials in CF patients aged 6 through 11 years who are homozygous for the F508del-CFTR mutation, a 24-week, open-label, multicenter Phase 3 safety trial in 58 patients (Trial 3) and a 24-week, placebo-controlled, Phase 3 clinical trial (Trial 4) in 204 patients (103 received lumacaftor 200 mg/ivacaftor 250 mg every 12 hours and 101 received placebo), was similar to that observed in Trials 1 and 2.

Adverse reactions that are not listed in Table 3, and that occurred in ≥5% of lumacaftor/ivacaftor-treated patients with an incidence of ≥3% higher than placebo included:

• productive cough (17.5% vs 5.9%),
• nasal congestion (16.5% vs 7.9%),
• headache (12.6% vs 8.9%),
• abdominal pain upper (12.6% vs 6.9%), and
• sputum increased (10.7% vs 2.0%).

In a 24-week, open-label, multicenter Phase 3 study in 60 patients aged 2 through 5 years with CF who are homozygous for the F508del-CFTR mutation (Trial 6) the safety profile was similar to that observed in studies in patients aged 6 years and older.

Additional information on selected adverse reactions from trials is detailed below.

Description Of Selected Adverse Drug Reactions

Liver-Related Adverse Reactions

In Trials 1 and 2, the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN elevations was similar between patients treated with Orkambi and those who received placebo. Three patients who received Orkambi had liver-related serious adverse reactions, including 2 reported as transaminase elevations and 1 as hepatic encephalopathy, compared to none in the placebo group.

Of these three, one had elevated transaminases (>3 x ULN) associated with bilirubin elevation >2 x ULN. Following discontinuation or interruption of Orkambi, transaminases decreased to <3 x ULN.

Among 6 patients with pre-existing cirrhosis and/or portal hypertension who received Orkambi, worsening liver function with increased ALT, AST, bilirubin, and hepatic encephalopathy was observed in one patient. The event occurred within 5 days of the start of dosing and resolved following discontinuation of Orkambi.

During the 24-week, open-label Phase 3 clinical trial in 58 patients aged 6 through 11 years (Trial 3), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 5%, 9%, and 19%. No patients had total bilirubin levels > 2 x ULN. Lumacaftor/ivacaftor dosing was maintained or successfully resumed after interruption in all patients with transaminase elevations, except 1 patient who discontinued treatment permanently.

During the 24 week, placebo-controlled Phase 3 clinical trial in 204 patients aged 6 through 11 years (Trial 4), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 1%, 5%, and 13% in the lumacaftor/ivacaftor patients, and 2%, 3%, and 8% in the placebo treated patients. No patients had total bilirubin levels > 2 x ULN. Two patients in the lumacaftor/ivacaftor group and two patients in the placebo group discontinued treatment permanently due to transaminase elevations.

During the 24-week, open-label Phase 3 clinical study in 60 patients aged 2 through 5 years (Trial 6), the incidence of maximum transaminase (ALT or AST) levels >8, >5, and >3 x ULN was 8.3% (5/60), 11.7% (7/60), and 15.0% (9/60). No patients had total bilirubin levels > 2 x ULN. Three patients discontinued lumacaftor/ivacaftor treatment permanently due to transaminase elevations.

Respiratory Adverse Reactions

In Trials 1 and 2, the incidence of respiratory symptom-related adverse reactions (e.g., chest discomfort, dyspnea, and respiration abnormal) was more common in patients treated with Orkambi (22%) compared to patients who received placebo (14%). The incidence of these adverse reactions was more common in patients treated with Orkambi with lower pre-treatment FEV₁. In patients treated with Orkambi, the majority of the events began during the first week of treatment .

Duringa 24-week, open label, Phase 3b clinicaltrialin 46 patients aged 12 yearsand older (Trial 5) with advanced lungdisease(ppFEV₁<40) [mean ppFEV₁29.1at baseline (range: 18.3 to 42.0)], the incidence of respiratory symptom-related adverse reactions was 65%.

During the 24-week, open-label Phase 3 clinical trial (Trial 3) in 58 patients aged 6 through 11 years (mean baseline ppFEV₁ was 91.4), the incidence of respiratory symptom-related adverse reactions was 3% (2/58).

During the 24 week, placebo-controlled Phase 3 clinical trial (Trial 4) in patients aged 6 through 11 years (mean ppFEV₁ 89.8 at baseline [range: 48.6 to 119.6]), the incidence of respiratory symptom-related adverse reactions was 11% in lumacaftor/ivacaftor patients and 9% in placebo patients. A decline in ppFEV₁ at initiation of therapy was observed during serial post dose spirometry assessments. The absolute change from pre-dose at 4-6 hours post-dose was -7.7 on Day 1 and -1.3 on Day 15 in lumacaftor/ivacaftor patients. The post-dose decline was resolved by Week 16.

Menstrual Abnormalities

In Trials 1 and 2, the incidence of combined menstrual abnormality adverse reactions (e.g., amenorrhea, dysmenorrhea, menorrhagia, menstrual irregular) was more common in female patients treated with Orkambi (10%) compared to placebo (2%). These events occurred more frequently in the subset of female patients treated with Orkambi who were using hormonal contraceptives (27%) compared to those not using hormonal contraceptives (3%).

Increased Blood Pressure

In Trials 1 and 2, adverse reactions related to increases in blood pressure (e.g., hypertension, blood pressure increased) were reported in 1.1% (4/369) of patients treated with Orkambi and in no patients who received placebo.

The proportion of patients who experienced a systolic blood pressure value >140 mmHg or a diastolic blood pressure >90 mmHg on at least two occasions was 3.6% and 2.2% in patients treated with Orkambi, respectively, compared with 1.6% and 0.5% in patients who received placebo.

Post-marketing Experience

Because post-marketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Post-marketing cases of liver function decompensation including liver failure leading to death have been reported in CF patients with pre-existing cirrhosis with portal hypertension who were treated with Orkambi.