Accepted answer
Your second candidate is right and it produces an exact answer. A two-week break drops exposure to what a 0.6 mg maintenance dose would produce, so resuming 2.4 mg is a four-fold step — larger than any rung on the ladder. The restart rule is protecting against a step-up bigger than the label ever asks anyone to take. Here is the derivation.
The equivalence trick
At steady state on dose X weekly with a 7-day half-life, the peak amount in the body is 2X in mass-equivalent terms, because the accumulation ratio is exactly 2. So any residual amount can be converted into "the dose that would have produced this level at steady state" by dividing by 2. That gives a common currency for comparing a break against a rung.
Take somebody at steady state on 2.4 mg weekly. Peak amount = 2 × 2.4 = 4.8 mg-equivalent.
| Weeks with no dose | Residual amount | Equivalent steady-state dose | Nearest rung on the ladder | Step-up factor to resume 2.4 mg |
|---|
| 0 (normal trough at 7 days) | 2.40 mg-eq | 1.2 mg | between 1.0 and 1.7 | 2.0 × |
| 1 (14 days since last dose) | 1.20 mg-eq | 0.60 mg | between 0.5 and 1.0 | 4.0 × |
| 2 (21 days) | 0.60 mg-eq | 0.30 mg | the 0.25 mg initiation rung | 8.0 × |
| 3 (28 days) | 0.30 mg-eq | 0.15 mg | below the initiation rung | 16 × |
| 4 (35 days) | 0.15 mg-eq | 0.075 mg | far below | 32 × |
Now compare against the ladder's own step sizes. Semaglutide goes 0.25 → 0.5 → 1.0 → 1.7 → 2.4, so the step factors are 2.0 ×, 2.0 ×, 1.7 × and 1.41 ×. The largest step the label ever asks for is a doubling, and it only asks for that at the bottom of the ladder where absolute exposure is lowest.
Read the two together and the rule falls out. One missed dose leaves you needing a 2.0 × step to resume — exactly the size of a labelled rung, at the bottom of the ladder, which is why a single missed dose is handled without ceremony. Two missed doses need a 4.0 × step, twice the largest labelled increment, at the top of the ladder where symptom burden is highest. That is the point at which the label stops treating it as a missed dose and starts treating it as a re-initiation.
The same calculation for a 15 mg tirzepatide maintenance dose, where the accumulation ratio is 1.61: peak = 1.61 × 15 = 24.2 mg-eq. After two missed weeks the residual is 24.2 × 2^(−21/5) = 24.2 × 0.0541 = 1.31 mg-eq, equivalent to a steady-state dose of 1.31 / 1.61 = 0.81 mg — below the 2.5 mg initiation rung. The shorter half-life makes the cliff steeper, which is consistent with tirzepatide's tighter missed-dose window.
What the table does not capture
Two things, and both matter.
Adaptation is not exposure. The reason a step-up factor is the relevant quantity at all is that gastrointestinal tolerance is a function of recent exposure history, not of current concentration. Somebody who has been at 2.4 mg for eight months has an adapted gastrointestinal system; three weeks off, and both the drug and the adaptation have partly gone, but there is no reason to assume they decay with the same time constant. The published data on this is thin — nobody has run a trial that interrupts maintenance and measures re-escalation tolerability — so the honest position is that the restart threshold is a conservative guess about a decay curve nobody has measured.
Resuming does not necessarily mean the bottom rung. The label language contemplates re-initiating escalation or resuming at the previously tolerated dose, which is a genuinely open instruction and one of the few places in the prescribing information where the sponsor declines to give a number. That is not sloppiness; it is an acknowledgement that a two-week break in someone who was six weeks into a ladder and a two-week break in someone stable for a year are different situations that a single rule would handle badly. It is precisely the kind of decision that belongs with a clinician who knows which of those two situations applies.
Contrast with the washout-based rule
The liraglutide weight-management label re-initiates at the starting dose after more than three days without a dose. With a 13-hour half-life, three days is 5.5 half-lives and leaves about 2 % of steady state. That is a washout rule — the drug really is gone. The weekly agents cannot use a washout rule, because washout would take five weeks or more, and a rule that permitted resuming a full dose after four weeks off would license a 32-fold step-up. So the weekly agents use a step-size rule instead. Same objective, two different derivations, dictated by half-life.
edited 3 Jul 2026 by orla_ferriter — expanded the table to cover the lower concentration
The step-up factor next to the labelled step sizes is the argument. Four-fold versus a maximum labelled doubling, and it is the top rung. That settles it. – tess_amankwah 9 months ago 2The observation that the label deliberately declines to give a number for what to resume at is worth its own thread. – tandem_gradient 26 days ago 3Nobody has run the interrupt-and-re-escalate trial, which is a striking gap given how common an interrupted supply is. – Dr_Bram_Verhoeven 6 months ago add a comment