‘Add-On’ Drugs Raise Questions About Safety and Cost

The following article was first published on SHARYL ATTKISSON‘s free Substack

Add-on drugs or “adjunctive therapies” offer new options for people who aren’t getting good results with a medicine
But add-ons introduce additional risks
And they dramatically add to medical costs
They also pose ethical dilemmas
Read list of use of adjunctive therapies in ten medical fields

If you watch television or Internet programming, you may have noticed that the trend of “add-on” drugs seems to be growing.

Add-on drugs are added onto existing treatments that aren’t working well. For example, when asthma patients aren’t getting good results with their inhalers for severe attacks, Tezspire by AstraZeneca may be recommended as an add-on. When cholesterol-lowering statins aren’t doing the job, Repatha by Amgen may be added on.

The financial stakes are high. Add-ons are heavily promoted by drugmakers, and experts are calling for more scrutiny to ensure patient care remains the priority over industry profits.

Read on for details.

The approach of using “add-on” drugs has become increasingly common in fields like oncology, cardiology, and respiratory medicine.

Advocates say it offers new options for complex conditions. But critics say the trend has harmful potential repercussions:

It keeps patients taking drugs that aren’t working well rather than recommending they stop the ineffective medicine and try something else
It could double (or more) the risk of side effects
It greatly increases costs
There are ethical concerns when a given add-on is made by the same company as the original drug

One obvious question you may have is: Why should patients continue taking a medicine that isn’t working well rather than simply trying another medicine, if available— or another treatment option entirely?

Supporters of add-ons say it’s because the original drug may still provide “some benefit” for patients. They also say that discontinuing it might worsen their symptoms. And doctors may prefer adding a drug “to avoid disruption.”

But critics say that taking multiple drugs, “polypharmacy,” increases the risk of interactions and side effects, potentially doubling them or more. The exponential increase in risks is a concern highlighted by some medical experts (NEJM Editorial).

The full risks of adding drugs may be understated or unknown, especially if the drugs haven’t been widely tested together over the longterm in the sick populations taking them. This lack of comprehensive testing, especially in real-world settings, underscores the need for more robust post-market surveillance, as noted in industry analyses.

Ethical issues arise when the same company, like AstraZeneca with Tezspire and asthma meds, produces both. It creates a conflict of interest scenario that may prioritize profits over suggesting alternatives such as finding an entirely different, more effective path of treatment.

Financial Gains

Add-on drugs are drawing in lots of cash while allowing the maker of the original drug to also continue to profit. Having a patient take two drugs, especially an add-on that’s newer, can dramatically increase costs ultitmately borne by taxpayers and patients.

Tezspire has reportedly been prescribed to over 100,000 patients since its launch and reached $500 million in first-year sales, as reported in AstraZeneca’s financial updates. Repatha has annual sales exceeding $1.5 billion, according to Amgen’s Q1 2023 earnings.

Medical journals have addressed this trend, with criticism focusing on effectiveness and ethics. A study in The New England Journal of Medicinehighlighted the potential for overuse of add-on therapies, suggesting they may be prescribed more for financial reasons than clinical necessity. Another article in JAMA found many add-on drugs offer only marginal benefits, questioning their cost-effectiveness.

Read Sharyl’s five star bestseller: “Follow the $cience: How Big Pharma Misleads, Obscures, and Prevails.”

Here’s a list of some adjunctive medicines and their usage in ten fields.

1. Mental Health Disorders

Adjunctive medications in psychiatry are used to enhance antidepressants, antipsychotics, or mood stabilizers, often for depression, bipolar disorder, schizophrenia, or anxiety.

Aripiprazole (Abilify)
- Primary Use: Antipsychotic
- Adjunctive Role: Added to antidepressants for treatment-resistant major depressive disorder (MDD) or to mood stabilizers for bipolar disorder to manage manic or depressive episodes.
Quetiapine (Seroquel)
- Primary Use: Antipsychotic
- Adjunctive Role: Combined with antidepressants for MDD or bipolar depression; used with lithium or valproate for bipolar mania.
Lithium
- Primary Use: Mood stabilizer
- Adjunctive Role: Added to antidepressants in MDD to augment response or to antipsychotics in schizophrenia for mood stabilization.
Lamotrigine (Lamictal)
- Primary Use: Anticonvulsant/mood stabilizer
- Adjunctive Role: Combined with lithium or other mood stabilizers in bipolar disorder to prevent depressive episodes; used off-label with antidepressants in MDD.
Bupropion (Wellbutrin)
- Primary Use: Antidepressant
- Adjunctive Role: Added to SSRIs (e.g., sertraline) in MDD to address sexual side effects or enhance mood; used off-label in ADHD with stimulants.
Buspirone (Buspar)
- Primary Use: Anxiolytic
- Adjunctive Role: Combined with SSRIs for generalized anxiety disorder (GAD) or MDD to reduce anxiety symptoms.
Brexpiprazole (Rexulti)
- Primary Use: Antipsychotic
- Adjunctive Role: Added to antidepressants for MDD or to other antipsychotics in schizophrenia for partial symptom control.

2. Attention-Deficit/Hyperactivity Disorder (ADHD)

Adjunctive medications enhance stimulants or address co-occurring conditions.

Atomoxetine (Strattera)
- Primary Use: Non-stimulant ADHD medication
- Adjunctive Role: Combined with stimulants (e.g., Adderall) to enhance attention or reduce stimulant dose in partial responders.
Clonidine (Kapvay)
- Primary Use: Non-stimulant ADHD medication
- Adjunctive Role: Used with stimulants to reduce impulsivity or manage stimulant side effects like insomnia.
- Notes: More sedating than guanfacine.
Guanfacine (Intuniv)

Primary Use: Non-stimulant ADHD medication
Adjunctive Role: Added to stimulants to manage hyperactivity or irritability; helps with sleep issues caused by stimulants.
Notes: Common in pediatric ADHD.

3. Neurology (Epilepsy, Migraine, Neuropathic Pain)

Adjunctive therapies in neurology are common for conditions requiring multiple drugs to control symptoms.

Levetiracetam (Keppra)
- Primary Use: Anticonvulsant
- Adjunctive Role: Added to other anticonvulsants (e.g., phenytoin) for partial or generalized seizures in epilepsy.
Topiramate (Topamax)
- Primary Use: Anticonvulsant
- Adjunctive Role: Combined with other anticonvulsants for epilepsy; used with propranolol or amitriptyline for migraine prevention.
Gabapentin (Neurontin)
- Primary Use: Anticonvulsant/neuropathic pain
- Adjunctive Role: Added to other anticonvulsants for epilepsy or to opioids/NSAIDs for neuropathic pain (e.g., diabetic neuropathy).
- Notes: Often used off-label for chronic pain.
Pregabalin (Lyrica)
- Primary Use: Anticonvulsant/neuropathic pain
- Adjunctive Role: Combined with gabapentin or antidepressants for neuropathic pain or fibromyalgia; used in epilepsy with other anticonvulsants.
OnabotulinumtoxinA (Botox)
- Primary Use: Neuromuscular agent
- Adjunctive Role: Added to oral prophylactics (e.g., topiramate) for chronic migraine prevention.

4. Oncology

Adjunctive medications in cancer treatment manage side effects, enhance chemotherapy, or target specific pathways.

Dexamethasone
- Primary Use: Corticosteroid
- Adjunctive Role: Combined with chemotherapy to reduce nausea, inflammation, or cerebral edema in brain tumors; used with immunotherapies to manage immune-related side effects.
Ondansetron (Zofran)
- Primary Use: Antiemetic
- Adjunctive Role: Added to chemotherapy regimens to prevent nausea and vomiting.
Filgrastim (Neupogen)
- Primary Use: Colony-stimulating factor
- Adjunctive Role: Used with chemotherapy to boost white blood cell counts and prevent infections.
Leuprolide (Lupron)
- Primary Use: GnRH agonist
- Adjunctive Role: Combined with chemotherapy or radiation in prostate or breast cancer to suppress hormone production.
Palbociclib (Ibrance)
- Primary Use: CDK4/6 inhibitor
- Adjunctive Role: Added to hormonal therapies (e.g., letrozole) in HR-positive breast cancer to slow tumor growth.

5. Cardiology

Adjunctive medications enhance primary treatments for heart failure, hypertension, or arrhythmias.

Spironolactone (Aldactone)
- Primary Use: Diuretic/aldosterone antagonist
- Adjunctive Role: Added to ACE inhibitors and beta-blockers in heart failure to reduce mortality and fluid overload.
Ezetimibe (Zetia)
- Primary Use: Cholesterol absorption inhibitor
- Adjunctive Role: Combined with statins to further lower LDL cholesterol in hyperlipidemia or post-myocardial infarction.
Amiodarone
- Primary Use: Antiarrhythmic
- Adjunctive役: Added to beta-blockers or other antiarrhythmics for atrial fibrillation or ventricular tachycardia.
Sacubitril/Valsartan (Entresto)
- Primary Use: Angiotensin receptor-neprilysin inhibitor
- Adjunctive Role: Used with beta-blockers or diuretics in heart failure with reduced ejection fraction to improve outcomes.
- Notes: Not a first-line therapy but enhances standard care.

6. Infectious Diseases

Probenecid
- Primary Use: Uricosuric agent
- Adjunctive Role: Combined with antibiotics (e.g., penicillin) to prolong their serum levels by reducing renal excretion.
Ritonavir
- Primary Use: Protease inhibitor
- Adjunctive Role: Used as a pharmacokinetic booster with other antiretrovirals (e.g., lopinavir) in HIV treatment to increase drug levels.
Corticosteroids (e.g., Prednisone)
- Primary Use: Anti-inflammatory
- Adjunctive Role: Added to antibiotics in severe infections (e.g., bacterial meningitis, tuberculosis) to reduce inflammation or prevent complications.
Zinc Supplements
- Primary Use: Nutritional supplement
- Adjunctive Role: Combined with antimalarials or antibiotics in certain infections to enhance immune response.

7. Pain Management

Adjunctive medications enhance analgesics or address neuropathic components of pain.

Duloxetine (Cymbalta)
- Primary Use: Antidepressant (SNRI)
- Adjunctive Role: Added to opioids or NSAIDs for chronic pain (e.g., fibromyalgia, osteoarthritis) to address neuropathic components.
Lidocaine (Topical or IV)
- Primary Use: Local anesthetic
- Adjunctive Role: Used with opioids for postoperative pain or neuropathic pain (e.g., postherpetic neuralgia).
Ketamine
- Primary Use: Anesthetic
- Adjunctive Role: Low-dose IV infusion added to opioids for chronic pain or acute postoperative pain to reduce opioid requirements.
Methocarbamol (Robaxin)
- Primary Use: Muscle relaxant
- Adjunctive Role: Combined with NSAIDs or opioids for musculoskeletal pain to relieve muscle spasms.
Gabapentin (Neurontin)
- Primary Use: Anticonvulsant/neuropathic pain
- Adjunctive Role: Added to other anticonvulsants for epilepsy or to opioids/NSAIDs for neuropathic pain (e.g., diabetic neuropathy).
- Notes: Often used off-label for chronic pain.

8. Autoimmune and Inflammatory Diseases

Hydroxychloroquine (Plaquenil)
- Primary Use: Antimalarial/immunomodulator
- Adjunctive Role: Added to methotrexate or biologics in rheumatoid arthritis or lupus to reduce disease activity.
Azathioprine (Imuran)
- Primary Use: Immunosuppressant
- Adjunctive Role: Combined with corticosteroids or biologics in autoimmune diseases (e.g., Crohn’s disease, lupus) to reduce steroid doses.
Apremilast (Otezla)
- Primary Use: PDE4 inhibitor
- Adjunctive Role: Used with DMARDs or biologics in psoriatic arthritis to manage joint and skin symptoms.

9. Asthma/COPD

Symbicort (budesomide)
- Adjunctive Role: Combined with inhaled steroids and bronchodilators.
Tezspire (teztrema)
- Adjunctive Role: Combined with inhaled corticosteroids
Xolair (omalizumab)
- Adjunctive Role: Combined with inhaled corticosteroids
Dupixent (dupilumab)
- Adjunctive Role: Combined with inhaled corticosteroids